5ht2c receptor modulators

ABSTRACT

The present invention relates to novel compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     which act as 5HT 2C  receptor modulators. These compounds are useful in pharmaceutical compositions whose use includes the treatment of obesity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/410,991, filedApr. 10, 2003, which in turn claims priority benefit of U.S. ProvisionalApplication No. 60/372,058, filed Apr. 12, 2002; U.S. Provisional PatentApplication No. 60/405,495, filed Aug. 23, 2002 and U.S. ProvisionalPatent Application No. 60/434,607, filed Dec. 18, 2002 which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds which act as modulators of5HT_(2C) receptors, compositions including the compounds, and methods ofusing the compounds.

BACKGROUND OF THE INVENTION

Obesity is a life-threatening disorder in which there is an increasedrisk of morbidity and mortality arising from concomitant diseases suchas type II diabetes, hypertension, stroke, cancer and gallbladderdisease.

Obesity is now a major healthcare issue in the Western World andincreasingly in some third world countries. The increase in numbers ofobese people is due largely to the increasing preference for high fatcontent foods but also, and this can be a more important factor, thedecrease in activity in most people's lives. In the last 10 years therehas been a 30% increase in the incidence of obesity in the USA and thatabout 30% of the population of the USA is now considered obese.

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m² (see TABLE below).

CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI) BMI CLASSIFICATION<18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight 30.0-34.9Obesity (Class I) 35.0-39.9 Obesity (Class II) >40 Extreme Obesity(Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases with obesity are cardiovascular disease (particularlyhypertension), diabetes (obesity aggravates the development ofdiabetes), gall bladder disease (particularly cancer) and diseases ofreproduction. Research has shown that even a modest reduction in bodyweight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

There are problems however with the BMI definition in that it does nottake into account the proportion of body mass that is muscle in relationto fat (adipose tissue). To account for this, obesity can also bedefined on the basis of body fat content: greater than 25% in males and30% in females.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight. Thediabetes patient faces a 30% reduced lifespan. After age 45, people withdiabetes are about three times more likely than people without diabetesto have significant heart disease and up to five times more likely tohave a stroke. These findings emphasize the inter-relations betweenrisks factors for NIDDM and coronary heart disease and the potentialvalue of an integrated approach to the prevention of these conditionsbased on the prevention of obesity (Perry, I. J., et al., BMJ 310,560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

The first line of treatment is to offer diet and life style advice topatients such as reducing the fat content of their diet and increasingtheir physical activity. However many patients find this difficult andneed additional help from drug therapy to maintain results from theseefforts.

Most currently marketed products have been unsuccessful as treatmentsfor obesity owing to a lack of efficacy or unacceptable side-effectprofiles. The most successful drug so far was the indirectly acting5-hydroxytryptamine (5-HT) agonist d-fenfluramine (Redux™) but reportsof cardiac valve defects in up to one third of patients led to itswithdrawal by the FDA in 1998.

In addition, two drugs have recently been launched in the USA andEurope: Orlistat (Xenical™), a drug that prevents absorption of fat bythe inhibition of pancreatic lipase, and Sibutramine (Reductil™), a5-HT/noradrenaline re-uptake inhibitor. However, side effects associatedwith these products may limit their long-term utility. Treatment withXenical™ is reported to induce gastrointestinal distress in somepatients, while Sibutramine has been associated with raised bloodpressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in numerousphysiological processes both in health and in psychiatric disorders.5-HT has been implicated in the regulation of feeding behavior for sometime. 5-HT appears to work by inducing a feeling of fullness or satietyso eating stops earlier and fewer calories are consumed. It has beenshown that a stimulatory action of 5-HT on the 5HT_(2C) receptor playsan important role in the control of eating and in the anti-obesityeffect of d-fenfluramine. As the 5-HT_(2C) receptor is expressed in highdensity in the brain (notably in the limbic structures, extrapyramidalpathways, thalamus and hypothalamus i.e. PVN and DMH, and predominantlyin the choroid plexus) and is expressed in low density or is absent inperipheral tissues, a selective 5-HT_(2C) receptor agonist can be a moreeffective and safe anti-obesity agent. Also, 5-HT_(2C) knockout mice areoverweight with cognitive impairment and susceptibility to seizure.

It is believed that 5HT_(2C) may play a role in obsessive compulsivedisorder, some forms of depression, and epilepsy. Accordingly, agonistscan have anti-panic properties, and properties useful for the treatmentof sexual dysfunction.

In sum, the 5HT_(2C) receptor is a validated and well-accepted receptortarget for the treatment of obesity and psychiatric disorders, and itcan be seen that there is a need for selective 5HT_(2C) agonists whichsafely decrease food intake and body weight. The present invention isdirected to these, as well as other, important ends.

SUMMARY OF THE INVENTION

The present invention, in one aspect, relates to compounds representedby Formula (I):

wherein:

R₁ is H or C₁₋₈ alkyl;

R₂ is C₁₋₈ alkyl, —CH₂—O—C₁₋₈ alkyl, —C(═O)—O—C₁₋₈alkyl,—C(═O)—NH—C₁₋₈alkyl, or CH₂OH;

R_(2a) is H or CH₃;

-   -   or R₂ and R_(2a) together form —CH₂—CH₂—;

R₃ and R₄ are each independently H, halogen, perhalo alkyl, (preferablyCF₃), CN, OR₅, SR₅, NHR₅, N(R₅)₂, aryl, or heteroaryl, wherein said arylcan be optionally substituted with up to two substituents selected fromC₁₋₈ alkyl, halogen and alkoxy, and said heteroaryl can be optionallysubstituted with up to two substituents selected from halogen and C₁₋₈alkyl;

-   -   or R₃ and R₄ together with the atoms to which they are attached        can form a 5- or 6-member heterocyclic ring having one O atom;    -   each R₅ is independently C₁₋₈alkyl, C₁₋₈alkenyl, aryl,        heteroaryl, arylalkyl, heteroarylalkyl or perhaloalkyl; and    -   R₆ is H or C₁₋₈alkyl; or a pharmaceutically acceptable salt,        solvate or hydrate thereof    -   provided that:    -   (A) if R₂ is methyl and R₁ and R₃ are both H, then R₄ is not        thiazole, substituted thiazole or a thiazole derivative:    -   (B) if R₆ is other than H, then neither R₃ nor R₄ can be H;    -   (C) if R₁ and R₂ are methyl, and R₄ is H, then R₃ cannot be NHR₅        or N(R₅)₂;    -   (D) if R₁ and R₂ are methyl, and R₄ is H, then R₃ cannot be        imidazole, substituted imidazole, or an imidazole derivative;        and    -   (E) if R₃ is OH, and R₁, is methyl then R₂ cannot be        cyclopentyl, —CH₂-cyclohexyl, cyclopropylmethyl, or cyclohexyl.    -   In some embodiments of the compounds and methods of the        invention, when R₁, R_(2a), R₃ and R₆ are H and R₂ is methyl,        then R₄ cannot be a chlorine atom.    -   In other embodiments of the compounds and methods of the        invention, when R₁, R_(2a), R₃ and R₆ are H and R₂ is methyl,        then R₄ can be a chlorine atom.

In some alternate embodiments of the compounds of Formula (I), if R₄ isOR₅, then R₂ cannot be alkyl.

In some embodiments of the compounds of Formula (I), R₁ is H. In someembodiments of the compounds of Formula (I), R₁ is C₁₋₈alkyl. In someembodiments of the compounds of Formula (I), R₁ is methyl. In someembodiments of the compounds of Formula (I), R₁ is n-propyl.

In some embodiments of the compounds of Formula (I), R₂ is C₁₋₈ alkyl.In some embodiments of the compounds of Formula (I), R₂ is methyl. Insome embodiments of the compounds of Formula (I), R₂ is ethyl. In someembodiments of the compounds of Formula (I), R₂ is isopropyl. In someembodiments of the compounds of Formula (I), R₂ and R_(2a) together form—CH₂—CH₂—.

In some embodiments of the compounds of Formula (I), R₃ is halogen. Insome embodiments of the compounds of Formula (I), R₃ is chlorine. Insome embodiments of the compounds of Formula (I), R₃ is bromine. In someembodiments of the compounds of Formula (I), R₃ is iodine. In someembodiments of the compounds of Formula (I), R₃ is perhaloalkyl. In someembodiments of the compounds of Formula (I), R₃ is CF₃. In someembodiments of the compounds of Formula (I), R₃ is a 5-memberedheteroaryl ring having up to two heteroatoms selected from O, N and S.In some embodiments, R₃ is a radical derived from thiophenyl, furanyl,pyrrolyl, pyrazolyl or imidazolyl.

In some embodiments of the compounds of Formula (I), R₄ is perhaloalkyl.In some embodiments of the compounds of Formula (I), R₄ is CF₃. In someembodiments of the compounds of Formula (I), R₄ is —OR₅. In someembodiments R₅ is methyl, ethyl, n-propyl, isopropyl or allyl. In someembodiments of the compounds of Formula (I), R₅ is methyl or allyl. Insome embodiments of the compounds of Formula (I), R₄ is a 5-memberedheteroaryl ring having up to two heteroatoms selected from O, N and S,and up to two substituents selected from halogen and C₁₋₈alkyl. In someembodiments, R₄ is a radical derived from thiophenyl, furanyl, pyrrolyl,pyrazolyl or imidazolyl, which can optionally be mono- or di-substitutedselected from halogen or methyl. In some embodiments of the compounds ofFormula (I), R₄ is phenyl optionally substituted with up to twosubstituents selected from C₁₋₈ alkyl, halogen, and alkoxy. In someembodiments of the compounds of Formula (I), R₃ and R₄ taken togetherform —O—CH═C(CH₃)—.

In some embodiments of the compounds of Formula (I), R₃ is halogen andR₄ is —OR₅ wherein R₅ is C₁₋₈alkyl. In some embodiments of the compoundsof Formula (I), R₃ is chlorine and R₄ is —OR₅ wherein R₅ is C₁₋₈ alkyl.In some embodiments of the compounds of Formula (I), R₃ is bromine andR₄ is —OR₅ wherein R₅ is C₁₋₈alkyl. In some embodiments of the compoundsof Formula (I), R₃ is iodine and R₄ is —OR₅ wherein R₅ is C₁₋₈ alkyl. Insome embodiments of the compounds of Formula (I), R₃ is halogen and R₄is methoxy. In some embodiments of the compounds of Formula (I), R₃ ishalogen and R₄ is allyloxy.

In some embodiments of the compounds of Formula (I), R₃ is H and R₄ is a5-membered heteroaryl ring having up to two heteroatoms selected from O,N and S, and up to two substituents selected from halogen and C₁₋₈alkyl,or R₄ is phenyl optionally substituted with up to two substituentsselected from C₁₋₈alkyl, halogen, and alkoxy.

In some embodiments of the compounds of Formula (I), R₃ is H and R₄ is adisubstituted pyrrazole or monohalo-substituted phenyl. In some suchembodiments of the compounds of Formula (I), the substitutents of thepyrrazole are bromine and methyl.

In some embodiments of the compounds of Formula (I), R₃ is OR₅. In someembodiments of the compounds of Formula (I), R₃ is OR₅ wherein R₅ isC₁₋₈alkyl. In some embodiments of the compounds of Formula (I), R₃ isOR₅ wherein R₅ is aryl. In some embodiments of the compounds of Formula(I), R₃ is OR₅ wherein R₅ is heteroaryl. In some embodiments of thecompounds of Formula (I), R₃ is OR₅ wherein R₅ is arylalkyl. In someembodiments of the compounds of Formula (I), R₃ is OR₅ wherein R₅ isarylmethyl. In some embodiments of the compounds of Formula (I), R₃ isOR₅ wherein R₅ is heteroarylalkyl. In some embodiments of the compoundsof Formula (I), R₃ is OR₅ wherein R₅ is heteroarylmethyl. In someembodiments of the compounds of Formula (I), R₃ is OR₅ wherein R₅ isperhaloalkyl. In some embodiments of the compounds of Formula (I), R₃ isOR₅ wherein R₅ is allyl.

In some embodiments of the compounds of Formula (I):

-   -   R₂ is methyl, ethyl, isopropyl, or CH₂OH; or R₂ and R_(2a) taken        together form —CH₂—CH₂—;    -   R₃ is H, halogen, or a 5-membered heteroaryl ring having up to        two heteroatoms selected from O, N and S, and up to two        substituents selected from halogen and C₁₋₈alkyl;

R₄ is H, alkoxy, a 5-membered heteroaryl ring having up to twoheteroatoms selected from O, N and S and up to two substituents selectedfrom halogen and C₁₋₈ alkyl, or phenyl optionally substituted with up totwo substituents selected from C₁₋₈ alkyl, halogen, and alkoxy;

-   -   or R₃ and R₄ taken together form —O—CH═C(CH₃)—; and    -   R₆ is H or methyl; or a pharmaceutically acceptable salt,        solvate or hydrate thereof.

In some embodiments of the compounds of Formula (I):

-   -   R₂ is methyl, ethyl, isopropyl, or CH₂OH; or R₂ and R_(2a) taken        together form —CH₂—CH₂—;    -   R₃ is chlorine, bromine, or iodine;    -   R₄ is alkoxy; and    -   R₆ is H or methyl; or a pharmaceutically acceptable salt,        solvate or hydrate thereof.

In some embodiments of the compounds of Formula (I):

-   -   R₁ is H;    -   R₂ is methyl;    -   R₃ is H, chlorine, bromine, or thiophene;    -   R₄ is alkoxy, pyrrazoly-3-yl or phenyl wherein said pyrrazole        optionally has up to two substituents selected from halogen and        C₁₋₈alkyl, and said phenyl optionally has a single halogen        substitutent; and    -   R₆ is H; or a pharmaceutically acceptable salt, solvate or        hydrate thereof.

In some embodiments of the compounds of Formula (I), the compound is amember of the group consisting of:8-Bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-Propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;3,5-Dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene;7-Allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-methoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(3-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-Methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;1-Methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;N-Propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;I-Ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(3-Methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2,6-difluorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-fluorophenyl)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(3-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(4-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments of the compounds of Formula (I), the compound is amember of the group consisting of:8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-7-methoxy-1-methyl-2,3,4,5-taetrhydro-1H-3-benzazepine;N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;and7-Methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments of the compounds of Formula (I), the compound is amember of the group consisting of:8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7,8-Dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and8-Chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or apharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides compositions comprising one or morecompounds of the invention, and one or more pharmaceutically acceptablecarriers.

The present invention further provides methods of modulating a 5HT_(2C)receptor comprising contacting said receptor with a pharmaceuticallyeffective amount of a compound or composition of the invention.Preferably, said compound is an agonist of said receptor.

The present invention further provides methods of prophylaxis ortreatment of disorders of the central nervous system; damage to thecentral nervous system; cardiovascular disorders; gastrointestinaldisorders; diabetes insipidus, and sleep apnea comprising administeringto a patient in need of such prophylaxis or treatment an effective doseof a compound of the invention.

In some embodiments, the disorders of the central nervous system includedepression, atypical depression, bipolar disorders, anxiety disorders,obsessive-compulsive disorders, social phobias or panic states, sleepdisorders, sexual dysfunction, psychoses, schizophrenia, migraine andother conditions associated with cephalic pain or other pain, raisedintracranial pressure, epilepsy, personality disorders, age-relatedbehavioral disorders, behavioral disorders associated with dementia,organic mental disorders, mental disorders in childhood, aggressivity,age-related mental disorders, chronic fatigue syndrome, drug and alcoholaddiction, obesity, bulimia, anorexia nervosa and premenstrual tension.In some embodiments, the disorders of the central nervous system isobesity.

In some embodiments, the damage to the central nervous system is bytrauma, stroke, neurodegenerative diseases or toxic or infective CNSdiseases, including encephalitis and meningitis.

In some embodiments, the cardiovascular disorder thrombosis. In furtherembodiments, the gastrointestinal disorder is dysfunction ofgastrointestinal motility.

The present invention further provides methods of decreasing food intakeof a mammal comprising administering to said mammal a pharmaceuticallyeffective amount of a compound or composition of the invention.

The present invention further provides methods of inducing satiety in amammal comprising administering to said mammal a pharmaceuticallyeffective amount of a compound or composition of the invention.

The present invention further provides methods of controlling weightgain of a mammal comprising administering to said mammal apharmaceutically effective amount of a compound or composition of theinvention.

The present invention further provides methods of treating obesitycomprising administering to a patient in need of such treatment apharmaceutically effective amount of a compound or composition of theinvention.

In some embodiments, some of the foregoing methods of the inventionfurther comprising the step of identifying a subject, said subject beingin need of decreasing food intake, controlling weight gain, or treatingobesity, wherein said identifying step is performed prior toadministering to said subject said pharmaceutically effective amount ofsaid compound or composition of the invention.

One aspect of the present invention pertains to a compound of Formula(I) for use in a method of treatment of the human or animal body bytherapy.

One aspect of the present invention pertains to a compound of Formula(I) for use in a method of prophylaxis or treatment of disorders of thecentral nervous system; damage to the central nervous system;cardiovascular disorders; gastrointestinal disorders; diabetesinsipidus, and sleep apnea. In some embodiments the disorders of thecentral nervous system are selected the group consisting of depression,atypical depression, bipolar disorders, anxiety disorders,obsessive-compulsive disorders, social phobias or panic states, sleepdisorders, sexual dysfunction, psychoses, schizophrenia, migraine andother conditions associated with cephalic pain or other pain, raisedintracranial pressure, epilepsy, personality disorders, age-relatedbehavioral disorders, behavioral disorders associated with dementia,organic mental disorders, mental disorders in childhood, aggressivity,age-related memory disorders, chronic fatigue syndrome, drug and alcoholaddiction, obesity, bulimia, anorexia nervosa and premenstrual tension.In some embodiments the disorder is obesity.

One aspect of the present invention pertains to a compound of Formula(I) for the manufacture of a medicament for use in the propylaxis ortreatment of disorders of the central nervous system; damage to thecentral nervous system; cardiovascular disorders; gastrointestinaldisorders; diabetes insipidus, and sleep apnea. In some embodiments thedisorders of the central nervous system are selected the groupconsisting of depression, atypical depression, bipolar disorders,anxiety disorders, obsessive-compulsive disorders, social phobias orpanic states, sleep disorders, sexual dysfunction, psychoses,schizophrenia, migraine and other conditions associated with cephalicpain or other pain, raised intracranial pressure, epilepsy, personalitydisorders, age-related behavioral disorders, behavioral disordersassociated with dementia, organic mental disorders, mental disorders inchildhood, aggressivity, age-related memory disorders, chronic fatiguesyndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosaand premenstrual tension. In some embodiments the disorder is obesity.

In some embodiments, the invention provides methods for alleviation of asymptom of any of the diseases, conditions or disorders mentionedherein.

Applicants reserve the right to exclude any one or more of the compoundsfrom any of the embodiments of the invention. Applicant additionallyreserves the right to exclude any disorder from any of the embodimentsof the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1G illustrate the effects of seven different compounds of theinvention on food intake in food-deprived rats.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 5HT_(2C) receptor agonist compounds,methods of modulating 5HT_(2C) receptors by contacting the receptorswith one or more compounds of the invention. The present invention alsorelates to methods of decreasing food intake, controlling weight gain,or treating obesity, using compounds of the invention.

The term “antagonist” is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist. As used herein, the term “agonist” isintended to mean moieties that activate the intracellular response whenthey bind to the receptor, or enhance GTP binding to membranes. In thecontext of the present invention, a pharmaceutical compositioncomprising a 5HT_(2C) receptor agonist of the invention can be utilizedfor modulating the activity of the 5HT_(2C) receptor, decreasing foodintake, inducing satiation (i.e., the feeling of fullness), controllingweight gain, treating obesity, decreasing body weight and/or affectingmetabolism such that the recipient loses weight and/or maintains weight.Such pharmaceutical compositions can be used in the context of disordersand/or diseases where weight gain is a component of the disease and/ordisorder such as, for example, obesity.

As used herein, the term “contact” or “contacting” shall mean bringingthe indicated moieties together, whether in an in vitro system or an invivo system. Thus, “contacting” an 5HT_(2C) receptor with a compound ofthe invention includes the administration of a compound of the inventionto an animal having an 5HT_(2C) receptor, as well as, for example,introducing a compound of the invention into a sample containing acellular or more purified preparation containing an 5HT_(2C) receptor.

Compounds of the invention include those having the Formula (I), shownbelow:

wherein:

R₁ is H or C₁₋₈alkyl;

R₂ is C₁₋₈ alkyl, —CH₂—O—C₁₋₈alkyl, —C(═O)—O—C₁₋₈alkyl,—C(═O)—NH—C₁₋₈alkyl, or CH₂OH;

R_(2a) is H; or R₂ and R_(2a) together form —CH₂—CH₂—;

R₃ and R₄ are each independently H, halogen, perhalo alkyl, (preferablyCF₃), CN, OR₅, SR₅, NHR₅, N(R₅)₂, aryl, or heteroaryl, wherein said arylcan be optionally substituted with up to two substituents selected fromC₁₋₈ alkyl, halogen and alkoxy, and said heteroaryl can be optionallysubstituted with up to two substituents selected from halogen andC₁₋₈alkyl;

-   -   or R₃ and R₄ together with the atoms to which they are attached        can form a 5- or 6-member heterocyclic ring having one O atom;

each R₅ is independently C₁₋₈ alkyl, C₁₋₈alkenyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl or perhaloalkyl; and

R₆ is H or C₁₋₈alkyl; or a pharmaceutically acceptable salt, solvate orhydrate thereof

provided that:

-   -   (A) if R₂ is methyl and R₁ and R₃ are both H, then R₄ is not        thiazole, substituted thiazole or a thiazole derivative:    -   (B) if R₆ is other than H, then neither R₃ nor R₄ can be H;    -   (C) if R₁ and R₂ are methyl, and R₄ is H, then R₃ cannot be NHR₅        or N(R₅)₂;    -   (D) if R₁ and R₂ are methyl, and R₄ is H, then R₃ cannot be        imidazole, substituted imidazole, or an imidazole derivative;        and    -   (E) if R₃ is OH, and R₁ is methyl then R₂ cannot be cyclopentyl,        —CH₂-cyclohexyl, cyclopropylmethyl, or cyclohexyl;    -   or provided (A), (B), (C), (D) above, and if R₄ is OR₅, then R₂        cannot be alkyl.    -   In some embodiments of the compounds and methods of the        invention, when R₁, R_(2a), R₃ and R₆ are H and R₂ is methyl,        then R₄ cannot be a chlorine atom.    -   In other embodiments of the compounds and methods of the        invention, when R₁, R_(2a), R₃ and R₆ are H and R₂ is methyl,        then R₄ can be a chlorine atom.

In some embodiments, if R₄ is OR₅, then R₂ cannot be cyclopentyl, —CH₂—cyclohexyl, 3,3-dimethyl-2-allyl, 3,3-dimethyl-2-methylallyl,2-methylallyl, 2-butenyl, cyclopropylmethyl, cyclohexyl, or allyl.

It will be appreciated that compounds of Formula (I) may have one ormore chiral centers, and exist as enantiomers or diastereomers. Theinvention is to be understood to extend to all such enantiomers,diastereomers and mixtures thereof, including racemates. Formula (I) andthe formulae hereinafter are intended to represent all individualisomers and mixtures thereof, unless stated or shown otherwise.

As used herein, the term “alkyl” is intended to denote hydrocarbongroups including straight chain, branched and cyclic hydrocarbons,including for example but not limited to methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl,cyclopropylmethyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl,cyclopentylmethyl, n-hexyl, cyclohexyl, and the like. Throughout thisspecification, it should be understood that the term alkyl is intendedto encompass both non-cyclic hydrocarbon groups and cyclic hydrocarbongroups. In some embodiments of the compounds of the invention, alkylgroups are non-cyclic. In further embodiments, alkyl groups are cyclic,and in further embodiments, alkyl groups are both cyclic and noncyclic.Where no preference is specified, the term “alkyl” is intended to denotegroups that are both cyclic and non-cyclic.

As used herein, the term “alkenyl” is intended to denote hydrocarboncompounds including straight chain, branched and cyclic hydrocarbonsthat contain at least one double bond, including for example but notlimited to allyl, 2-methyl-allyl, 4-but-3-enyl, 4-hex-5-enyl,3-methyl-but-2-enyl, cyclohex-2-enyl and the like.

As used herein, the term “halogen” has its normal meaning of periodseven elements, including F, Cl, Br and I.

The term “alkoxy” is intended to denote substituents of the formula—O-alkyl, including —O-allyl. The term “lower” when used in connectionwith substituents such as alkyl indicates 6 carbons or less.

The term “arylalkyl” or “aralkyl” is intended to denote an alkyl groupthat bears an aryl substituent, for example a benzyl group. The term“alkylaryl” or “alkaryl” is intended to denote an aryl group that bearsan alkyl substituent, for example a 4-methylphenyl group.

As used herein, the term “aryl” is intended to mean monocyclic andpolycyclic aromatic groups. Although aryl groups can include as few as 3carbon atoms, preferred aryl groups have 6 to about 14 carbon atoms,more preferably 6 to about 10 carbon atoms. Examples of aryl groupsinclude but are not limited to phenyl, naphthyl, anthracyl, phenanthryland pyrenyl.

The term “heteroaryl” is intended to denote an aryl group that containsat least one, and preferably from one to four ring “hetero” (i.e.,non-carbon, e.g., O, N or S) atom. Examples of “heteroaryl” groups areradicals derived from 5- and 6-member aryl ring compounds having fromone to four nitrogen, sulfur and/or oxygen atoms, for example pyrrole,pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, furan,pyran, thiophene, benzimidazole, quinoline, isoquinoline, oxazole,thiazole, and thiadiazole.

As used herein the term heteroarylalkyl means an alkyl group that bearsa heteroaryl substituent, for example a group having the structure—CH₂-pyrrole-2-yl.

The term “substituted thiazole” means a radical derived from thiazolethat bears at least one substituent group. The term “thiazolederivative” means a fused ring system in which one of the fused rings isthiazole.

The term “substituted imidazole” means a radical derived from imidazolethat bears at least one substituent group. The term “imidazolederivative” means a fused ring system in which one of the fused rings isimidazole.

In some embodiments of the invention, R₄ is OR₅. In some suchembodiments, R₂ cannot be cyclopentyl, —CH₂-cyclohexyl,3,3-dimethyl-2-allyl, 3,3-dimethyl-2-methylallyl, 2-methylallyl,2-butenyl, cyclopropylmethyl, cyclohexyl, or allyl. In further suchembodiments, R₂ cannot be alkyl.

In some embodiments of the compounds of Formula (I), R₃ is halogen andR₄ is —OR₅. In some embodiments of the compounds of Formula (I), R₅ isallyl, 2-methyl-allyl, 4-but-3-enyl, 4-hex-5-enyl, 3-methyl-but-2-enylor cyclohex-2-enyl. In some embodiments of the compounds of Formula (I),R₅ is methyl, ethyl, n-propyl, isopropyl or allyl. In some embodimentsof the compounds of Formula (I), R₅ is methyl or allyl.

Certain substituents of the compounds disclosed herein can optionally besubstituted, i.e., they can optionally bear further substituent groups.Some preferred substituent groups include halogen, lower alkyl(including but not limited to methyl, ethyl, isopropyl, cyclopropyl,tert-butyl, and methylcyclopropyl), alkoxy, mono-, di- or totrihaloalkoxy (e.g., —O—CX₃ where X is halogen), —(CH₂)_(y)NH₂,—(CH₂)_(y)NHBoc, —N(R_(4a))(R_(4b)), phenyl, methoxyphenyl and naphthyl.

At various places in the present specification substituents of compoundsof the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₈alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, C₆ alkyl, C₇ alkyland C₈ alkyl.

In a preferred embodiment, the compounds of Formula (I) are selectedfrom:

8-Bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-Propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;3,5-Dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene;7-Allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-7-methoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(3-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-Methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;1-Methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;N-Propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;1-Ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(3-Methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2,6-difluorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-fluorophenyl)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(2-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(3-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7-(4-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a preferred embodiment, the compounds of Formula (I) are selectedfrom:

N-methyl-8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Iodo-7-methoxy-1-methyl-2,3,4,5-taetrhydro-1H-3-benzazepine;N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Iodo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-7-Methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;andN-methyl-7-Methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a preferred embodiment, the compounds of Formula (I) are selectedfrom:

N-methyl-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-7,8-Dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;andN-methyl-8-Chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a preferred embodiment, the compounds of Formula (I) are selectedfrom:

8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-7-methoxy-1-methyl-2,3,4,5-taetrhydro-1H-3-benzazepine;N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine;7-Methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;and7-Methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a preferred embodiment, the compounds of Formula (I) are selectedfrom:

8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;7,8-Dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and8-Chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or apharmaceutically acceptable salt, solvate or hydrate thereof.

The compounds of the invention may contain one or more asymmetric carbonatoms, so that the compounds can exist in different stereoisomericforms. The compounds can be, for example, racemates or optically activeforms. The optically active forms can be obtained by resolution of theracemates or by asymmetric synthesis. In some embodiments, compounds ofFormula (I) are R enantiomers. In some embodiments, compounds of Formula(I) are S enantiomers. In some embodiments, compounds of Formula (I) arevarying mixtures of enantiomers.

According to a further aspect of the invention, compounds of Formula (I)are provided for use in therapy. The compounds of Formula (I) can beused in the prophylaxis or treatment of disorders associated with5-HT_(2C) receptor function.

The compounds of Formula (I) can be used in the prophylaxis or treatmentof central nervous disorders such as depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, age-related behavioral disorders, behavioraldisorders associated with dementia, organic mental disorders, mentaldisorders in childhood, aggressivity, age-related memory disorders,chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia,anorexia nervosa or premenstrual tension; damage of the central nervoussystem such as by trauma, stroke, neurodegenerative diseases or toxic orinfective CNS diseases such as encephalitis or meningitis;cardiovascular disorders such as thrombosis; gastrointestinal disorderssuch as dysfunction of gastrointestinal motility; diabetes insipidus;and sleep apnea.

According to a further aspect of the invention, there is provided use ofa compound of Formula (I) in the manufacture of a medicament for theprophylaxis or treatment of the disorders disclosed herein. In apreferred embodiment, there is provided a use of a compound of Formula(I) in the manufacture of a medicament for the prophylaxis or treatmentof obesity.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Such acids include acetic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric,succinic, sulfiric, tartaric, oxalic, p-toluenesulfonic and the like,such as the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) and incorporated herein byreference.

The acid addition salts can be obtained as the direct products ofcompound synthesis. In the alternative, the free base can be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compositions of the invention may conveniently be administered in unitdosage form and can be prepared by any of the methods well known in thepharmaceutical art, for example, as described in Remington'sPharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980).

The compounds of the invention can be employed as the sole active agentin a pharmaceutical or can be used in combination with other activeingredients which could facilitate the therapeutic effect of thecompound.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5HT_(2C) receptor agonists.By the term “active ingredient” is defined in the context of a“pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmaceuticalbenefit, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit. The term“pharmaceutical composition” shall mean a composition comprising atleast one active ingredient and at least one ingredient that is not anactive ingredient (for example and not limitation, a filler, dye, or amechanism for slow release), whereby the composition is amenable to usefor a specified, efficacious outcome in a mammal (for example, and notlimitation, a human).

The data developed herein supports the conclusion that the presentlydisclosed 5HT_(2C) receptor agonists are of use for the treatment orprophylaxis of clinical obesity or overweight disorders in mammals,including, but not limited to, human. Compounds of the present inventioncan be administered by oral, sublingual, parenteral, rectal, topicaladministration or by a transdermal patch. Transdermal patches dispense adrug at a controlled rate by presenting the drug for absorption in anefficient manner with a minimum of degradation of the drug. Typically,transdermal patches comprise an impermeable backing layer, a singlepressure sensitive adhesive and a removable protective layer with arelease liner. One of ordinary skill in the art will understand andappreciate the techniques appropriate for manufacturing a desiredefficacious transdermal patch based upon the needs of the artisan.

In addition to the neutral forms of compounds of the present invention,by appropriate addition of an ionizable substituent, which does notalter the receptor specificity of the compound, physiologicallyacceptable salts of the compounds may also be formed and used astherapeutic agents. Different amounts of the compounds of the presentinvention will be required to achieve the desired biological effect. Theamount will depend on factors such as the specific compound, the use forwhich it is intended, the means of administration, and the condition ofthe treated individual—all of these dosing parameters are within thelevel of one of ordinary skill in the medicinal arts. A typical dose canbe expected to fall in the range of 0.001 to 200 mg per kilogram of bodyweight of the mammal. Unit doses may contain from 1 to 200 mg of thecompounds of the present invention and can be administered one or moretimes a day, individually or in multiples.

Pharmaceutical compositions, including, but not limited to,pharmaceutical compositions, comprising at least one compound of thepresent invention and/or an acceptable salt or solvate thereof (e.g., apharmaceutically acceptable salt or solvate) as an active ingredientcombined with at least one carrier or excipient (e.g., pharmaceuticalcarrier or excipient) can be used in the treatment of clinicalconditions for which a 5HT_(2C) receptor agonist is indicated. At leastone compound of the present invention can be combined with the carrierin either solid or liquid form in a unit dose formulation. Thepharmaceutical carrier must be compatible with the other ingredients inthe composition and must be tolerated by the individual recipient. Otherphysiologically active ingredients can be incorporated into thepharmaceutical composition of the invention if desired, and if suchingredients are compatible with the other ingredients in thecomposition. Formulations can be prepared by any suitable method,typically by uniformly mixing the active compound(s) with liquids orfinely divided solid carriers, or both, in the required proportions, andthen, if necessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants can be used intablets and capsules for oral administration. Liquid preparations fororal administration can be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationscan be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants can be added to theliquid preparations. Parenteral dosage forms can be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

It is noted that when the 5HT_(2C) receptor agonists are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of 5HT_(2C) receptor agonists for thetreatment of obesity in domestic animals (e.g., cats and dogs), and5HT_(2C) receptor agonists in other domestic animals where no disease ordisorder is evident (e.g., food-oriented animals such as cows, chickens,fish, etc.). Those of ordinary skill in the art are readily creditedwith understanding the utility of such compounds in such settings.

The compounds of the present invention can be readily prepared accordingto a variety of synthetic manipulations, all of which would be familiarto one skilled in the art. A representative general synthesis is setforth below in Scheme I:

Those of skill in the art will appreciate that a wide variety ofcompounds of the invention can be prepared according to Scheme I. Forexample, by starting with an appropriately substituted 2-phenylethylamino compound A having any of a wide variety of substituents R₁and R₂, the corresponding 7- and/or 8-substituted1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (compound H) can beprepared. N-alkylation can be accomplished by, for example, treatmentwith excess paraformaldehyde (for methylation) or a higher orderaldehyde, followed by reduction with NaBH₃CN according to the generalprocedure of synthetic examples 9 and 10, infra. In addition, bystarting with an appropriately substituted 1-alkyl-2-phenyl ethylaminocompound A having any of a wide variety of substituents R₁ and R₂, thecorresponding 7- and/or 8-substituted2,5-dialkly-2,3,4,5-tetrahydro-1H-3-benzazepine compound can beprepared.

In the synthesis of many compounds of the invention, protecting groupscan be required to protect various functionality or functionalitiesduring the synthesis. Representative protecting groups suitable for awide variety of synthetic transformations are disclosed in Greene andWuts, Protective Groups in Organic Synthesis, 2d ed, John Wiley & Sons,New York, 1991, the disclosure of which is incorporated herein byreference in its entirety.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Synthetic Examples Example 1 (R,S)8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-3-methoxyphenethylamine

A solution of 3-methoxyphenethylamine (10.0 g, 64.0 mmol) indichloromethane (150 mL), was cooled to 0 C, and treated with pyridine(6.5 mL, 83.5 mmol) followed by the dropwise addition of trifluoraceticanhydride (17.9 g, 83.5 mmol) and the resulting mixture stirred for 3hours while warming to 20 C. The product mixture was diluted with EtOAc(500 mL), washed sequentially with 10% aqueous HCl (100 mL), water (100mL), brine (100 mL), dried with Na₂SO₄ and concentrated to give 15.8 gof a yellow oil. 1H NMR (400 MHz, CDCl₃) δ 7.26 (dd, J=8, 8 Hz, 1H),6.81 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 6.72 (s, 1H), 6.30 (bs, 1H),3.80 (s, 3H), 3.62 (dd, J=7, 7 Hz, 2H), 2.86 (dd, J=7, 7 Hz, 2H). MScalculated for C₁₁H₁₂F₃NO₂+H: 248. observed: 248.

N-Trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-3-methoxyphenethylamine (15.8 g, 64mmol) in methanol (325 mL) was cooled to −78 C, and treated with CaCO₃(14.7 g, 145 mmol), followed by a solution of ICl (29 g, 181 mmol) inmethanol (40 mL). The reaction was allowed to warm to 20 C whilestirring overnight and then filtered, concentrated, dissolved in EtOAc(200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), oncewith brine (100 mL), dried with Na₂SO₄ and concentrated to give 23.8 gof a white solid powder. 1H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=9 Hz, 1H),6.76 (s, 1H), 6.57 (d, J=9 Hz, 1H), 6.42 (bs, 1H), 3.77 (s, 3H), 3.61(dd, J=7, 7 Hz, 2H), 2.99 (dd, J=7, 7 Hz, 2H). MS calculated forC₁₁H₁₁F₃INO₂+H: 374. observed: 374.

N-Allyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (23.8 g,63.8 mmol) in toluene (425 mL) was sequentially treated with K₂CO₃ (12.4g, 89.8 mmol), KOH (11.6 g, 207 mmol), n-Bu₄NBr (2.2 g, 6.9 mmol) andallyl bromide (10.7 g, 89.8 mmol). The mixture was stirred at 80 C for3.5 hours, cooled to 20 C, acidified with 10% aqueous HCl, separated andthe aqueous phase extracted with ether (500 mL). The combined organicphases were washed with brine (200 mL), dried with Na₂SO₄ andconcentrated to give 20.5 g of a brown oil. 1H NMR (400 MHz, CDCl₃),mixture of rotamers d 7.67 (m, 1H), 6.80 (m, 1H), 6.57 (m, 1H), 5.9-5.6(bm, 1H), 5.27 (m, 2H), 4.11 (d, J=6 Hz, 0.5H), 3.85 (d, J=6 Hz, 0.5H),3.77 (m, 3H), 3.55 (m, 2H), 3.00 (m, 2H). MS calculated forC₁₄H₁₅F₃INO₂+H: 414. observed: 414.

N-Trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-allyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine(20.5 g, 50 mmol) in dimethylformamide (250 mL) is treated with KOAc(14.6 g, 149 mmol), n-Bu₄NBr (16.0 g, 50 mmol), PPh₃ (1.3 g, 5.0 mmol),Pd(OAc)₂ (0.56 g, 2.5 mmol) and stirred overnight at 90 C. The productmixture was cooled to 20 C, filtered, diluted with water (500 mL) andextracted with ether (3×500 mL). The combined organic phases were washedwith water (100 mL), brine (100 mL), dried with Na₂SO₄ and concentrated.Flash chromatography (10% EtOAc in hexane, silica) resulted in 6.6 g ofa yellow oil. 1H NMR (400 MHz, CDCl₃) δ 7.26 (d, J=8 Hz, 1H), 6.77 (d,J=8 Hz, 1H), 6.66 (s, 1H), 5.34-5.19 (m, 2H), 4.40 (m, 2H), 3.83 (m,2H), 3.80 (s, 3H), 3.00 (m, 2H). MS calculated for C₁₄H₁₄F₃NO₂+H: 285.observed: 285.

N-Trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-trihydro-1H-3-benzazepine(6.6 g, 23.2 mmol) in ethanol (100 mL), was treated with 10% Pd/C (0.75g, 2.3 mmol) and stirred overnight under an atmosphere of hydrogen. Theproduct mixture was filtered through a pad of celite and silica and thesolvent removed to give 6.27 g of a white solid. 1H NMR (400 MHz, CDCl₃,mixture of rotamers) d 7.10 (m, 1H), 6.74 (m, 1H), 6.68 (m, 1H), 4.1-3.8(bm, 2H), 3.8 (s, 3H), 3.5 (m, 1.5H), 3.4 (m, 0.5H), 3.2-2.9 (bm, 4H),1.32 (m, 3H). MS calculated for C₁₄H₁₆F₃NO₂+H: 288. observed: 288.

N-Trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.25 g, 4.35 mmol) in acetonitrile (40 mL) was treated withN-bromosuccinimide (0.852 g, 4.79 mmol) and stirred overnight at 20 C.The product mixture was diluted with EtOAc (200 mL), washed withsaturated aqueous sodium bisulfite (100 mL) and brine (100 mL), driedwith Na₂SO₄ and concentrated. Flash chromatography (15% EtOAc in hexane,silica) resulted in 1.55 g of a clear oil. 1H NMR (400 MHz, CDCl₃,mixture of rotamers) d 7.34 (s, 1H), 6.65 (m, 1H), 3.87 (s, 3H), 3.81(m, 1H), 3.55 (m, 1.3H), 3.37 (m, 0.7H), 3.2-2.9 (bm, 4H), 1.30 (m, 3H).MS calculated for C₁₄H₁₅BrF₃NO₂+H: 366. observed: 366.

8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.95 g, 2.59 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (25 mL), and stirred overnight at 20 C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.687 g of a clear oil. 1H NMR (400 MHz,CDCl₃) δ 7.92 (s, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.1-2.9 (m, 6H), 2.75(m, 1H), 2.60 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated forC₁₂H₁₆BrNO+H: 270. observed: 270.

Example 2 (R,S)8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.900 g, 2.67 mmol) in acetonitrile (30 mL) was treated withN-chlorosuccinimide (0.357 g, 2.67 mmol) and stirred overnight at 70 C.The product mixture was diluted with water (100 mL), extracted twicewith EtOAc (100 mL), the combined organic phases washed with brine (100mL), dried with Na₂SO₄ and concentrated. Flash chromatography (20% EtOAcin hexane, silica) resulted in 0.399 g of a clear oil. 1H NMR (400 MHz,CDCl₃, mixture of rotamers) d 7.17 (s, 1H), 6.68 (m, 1H), 3.88 (s, 3H),3.78 (m, 1H), 3.6-3.3 (m, 2H), 3.2-2.9 (m, 4H), 1.34 (m, 3H). MScalculated for C₁₄H₁₅ClF₃NO₂+H: 322. observed: 322.

8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.399 g, 1.24 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred overnight at 20 C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.306 g of a yellow solid. 1H NMR (400MHz, CDCl₃) δ 7.05 (s, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 3.0-2.8 (m, 6H),2.62 (m, 1H), 2.16 (bs, 1H), 1.24 (d, J=7 Hz, 3H). MS calculated forC₁₂H₁₆ClNO+H: 226. observed: 226.

Example 3 (R,S)8-Iodo-7-methoxy-1-methyl-2,3,4,5-taetrhydro-1H-3-benzazepine

N-Trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.50 g, 5.22 mmol) in methanol (70 mL) was treated with CaCO₃ (1.06 g,10.44 mmol) followed by a solution of ICl (1.70 g, 10.44 mmol) inmethanol (10 mL), and stirred overnight at 20 C. The product mixture wasfiltered, concentrated, dissolved in EtOAc (200 mL), extracted twicewith 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL),dried with Na₂SO₄ and concentrated. Flash chromatography (15% EtOAc inhexane, silica) resulted in 1.54 g of a white solid. 1H NMR (400 MHz,CDCl₃, mixture of rotamers) d 7.55 (m, 1H), 6.57 (m, 1H), 3.86 (s, 3H),3.80 (m, 1H), 3.60-3.30 (m, 2H), 3.20-2.80 (m, 4H), 1.30 (m, 3H). MScalculated for C₁₄H₁₅F₃INO₂+H: 414. observed: 414.

8-Iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-iodo7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.600 g, 1.45 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred for 3 hours at 50 C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.425 g of a yellow solid. 1H NMR (400MHz, CDCl₃) δ 7.52 (s, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 3.12-3.06 (m,4H), 2.95 (m, 2H), 2.75 (m, 1H), 2.43 (bs, 1H), 1.33 (d, J=8 Hz, 3H). MScalculated for C₁₂H₁₆INO+H: 318. observed: 318.

Example 4 (R,S)8-Bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.50 g, 4.10 mmol) in dichloromethane (80 mL) was treated dropwise withBBr₃ (9.4 mL of a 1.0M solution in CH₂Cl₂, 9.4 mmol), and the mixturestirred overnight while warming to 20 C. The excess BBr₃ was quenchedwith the dropwise addition of water, the mixture diluted with ether (200mL), washed with Na₂CO₃ (100 mL) and brine (100 mL), dried with Na₂SO₄and concentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 1.25 g of a white solid foam. 1H NMR (400 MHz, CDCl₃,mixture of rotamers) d 7.25 (s, 1H), 6.79 (m, 1H), 3.79 (m, 1H), 3.7-3.3(m, 2H), 3.2-2.8 (m, 4H), 1.32 (m, 3H).

8-Bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.655 g, 1.89 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred overnight at 20 C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.460 g of a clear oil. 1H NMR (400 MHz,DMSO-d₆) δ 7.11 (s, 1H), 6.65 (s, 1H), 2.90 (m, 1H), 2.73 (m, 5H), 2.55(m, 1H), 1.19 (d, J=7 Hz, 3H). MS calculated for C₁₁H₁₄BrNO+H: 256.observed: 256.

Example 5 (R,S)7-Allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.150 g, 0.426 mmol) in dichloromethane (5 mL) was treated with allylbromide (0.155 g, 1.28 mmol) and DBU (0.195 g, 1.28 mmol) and thenstirred 2 hours at 20 C. The product mixture was diluted with EtOAc (50mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (15% EtOAc in hexane,silica) resulted in 0.149 g of a clear oil. 1H NMR (400 MHz, CDCl₃,mixture of rotamers) d 7.34 (s, 1H), 6.65 (m, 1H), 6.04 (m, 1H), 5.47(d, J=17 Hz, 1H), 5.30 (d, J=9 Hz, 1H), 4.59 (s, 2H), 3.80 (m, 1H),3.6-3.3 (m, 3H), 3.2-2.8 (m, 4H), 1.31 (m, 3H). MS calculated forC₁₆H₁₇BrF₃NO₂+H: 392. observed: 392.

7-Allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.18 g, 3.00 mmol) in methanol (35 mL) was treated with 15% aqueousNaOH (35 mL), and stirred overnight at 20 C. The product mixture wasdiluted with water (200 mL), extracted twice with EtOAc (200 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.880 g of a clear oil. 1H NMR (400 MHz,CDCl₃) δ 7.29 (s, 1H), 6.63 (s, 1H), 6.04 (m, 1H), 5.47 (d, J=17 Hz,1H), 5.29 (d, J=11 Hz, 1H), 4.58 (s, 2H), 3.01 (m, 3H), 2.89 (m, 3H),2.75 (m, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated for C₁₄H₁₈BrNO+H: 296.observed: 296.

Example 6 (R,S)7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.075 g, 0.213 mmol) in dichloromethane (5 mL) was treated with benzylbromide (0.072 g, 0.64 mmol), DBU (0.100 g, 0.64 mmol), and stirred 2hours at 20 C. The product mixture was diluted with EtOAc (50 mL),washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.081 g of a clear oil. MS calculated for C₂₀H₁₉BrF₃NO₂+H:442. observed: 442.

7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.81 g, 1.83 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred overnight at 20 C. The product mixture wasdiluted with water (200 mL), extracted twice with EtOAc (200 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.412 g of a clear oil. 1H NMR (400 MHz,CDCl₃) δ 7.38 (d, J=8 Hz, 2H), 7.30 (dd, J=7, 8 Hz, 2H), 7.23 (m, 2H),6.61 (s, 1H), 5.03 (s, 2H), 2.94 (m, 3H), 2.81 (m, 3 H), 2.62 (m, 1H),2.30 (bs, 1H), 1.24 (d, J=7 Hz, 3H). MS calculated for C₁₈H₂₀BrNO+H:346. observed: 346.

Example 7 (R,S)8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.015 g, 0.043 mmol) in dichloromethane (1 mL) was treated with ethyliodide (0.016 g, 0.102 mmol), DBU (0.016 g, 0.102 mmol) and stirred 2hours at 20 C. The product mixture was diluted with EtOAc (10 mL),washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.010 g of a clear oil.

8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.010 g, 0.026 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred overnight at 20 C. The product mixture wasdiluted with water (3 mL), extracted twice with EtOAc (5 mL), thecombined organic phases were washed with brine (3 mL), dried with Na₂SO₄and concentrated to give 0.007 g of a clear oil. 1H NMR (400 MHz, CDCl₃)δ 7.29 (s, 1H), 6.63 (s, 1H), 4.07 (q, J=6 Hz, 2H), 3.03 (m, 3H), 2.91(m, 3H), 2.73 (m, 1H), 2.26 (bs, 1H), 1.46 (t, J=6 Hz, 3H), 1.32 (d, J=7Hz, 3H). MS calculated for C₁₅H₁₇BrF₃NO₂+H: 380. observed: 380.

Example 8 (R,S)8-Bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.035 g, 0.099 mmol) in dichloromethane (1 mL) was treated withisopropyl bromide (0.037 g, 0.297 mmol), DBU (0.048 g, 0.205 mmol) andstirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄and concentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.014 g of a clear oil. MS calculated for C₁₆H₁₉BrF₃NO₂+H:394. observed: 394.

8-Bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.014 g, 0.035 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred overnight at 20 C. The product mixture wasdiluted with water (3 mL), extracted twice with EtOAc (5 mL), thecombined organic phases were washed with brine (3 mL), dried with Na₂SO₄and concentrated to give 0.008 g of a clear oil. 1H NMR (400 MHz, CDCl₃)δ 7.24 (s, 1H), 6.64 (s, 1H), 4.48 (m, 1H), 2.98 (m, 3H), 2.87 (m, 3H),1.36 (m, 6H), 1.30 (d, J=7 Hz, 3H). MS calculated for C₁₄H₂₀BrNO+H: 298.observed: 298.

Example 9 (R,S)N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6 mg,0.022 mmol) in methanol (1 mL) was treated with excess paraformaldehyde,1.0 M HCl in ether (0.004 mL, 0.004 mmol), NaBH₃CN (1.0 mg, 0.013 mmol),and stirred overnight at 20 C. The product mixture was diluted with 5%aqueous NaOH (5 mL), extracted 3 times with CH₂Cl₂ (5 mL each), thecombined organic phases were dried with Na₂SO₄ and concentrated. Flashchromatography (10% MeOH in CH₂Cl₂, silica) resulted in 5 mg of a clearoil. 1H NMR (400 MHz, CDCl₃) δ 7.31 (s, 1H), 6.66 (s, 1H), 3.87 (s, 3H),3.26 (bm, 2H), 3.01 (bs, 1H), 2.85 (m, 2H), 2.45 (s, 3H), 2.45-2.25 (m,2H), 1.36 (d, J=7 Hz, 3H). MS calculated for C₁₃H₁₈BrNO+H: 284.observed: 284.

Example 10 (R,S)N-Propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of8-Bromo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (6 mg,0.022 mmol) in methanol (1 mL) was treated with propionaldehyde (5.0 mg,0.067 mmol), 1.0 M HCl in ether (0.004 mL, 0.004 mmol), NaBH₃CN (1.0 mg,0.013 mmol), and stirred overnight at 20 C. The product mixture wasdiluted with 5% aqueous NaOH (5 mL), extracted 3 times with CH₂Cl₂ (5 mLeach), the combined organic phases were dried with Na₂SO₄ andconcentrated. Flash chromatography (10% MeOH in CH₂Cl₂, silica) resultedin 4 mg of a clear oil. 1H NMR (400 MHz, CD₃OD) d 7.33 (s, 1H), 6.87 (s,1H), 3.84 (s, 3H), 3.25 (m, 2H), 3.11 (m, 2H), 2.97 (m, 1H), 2.78 (bm,2H), 2.63 (bm, 2H), 1.67 (m, 2H), 1.38 (d, J=7 Hz, 3H), 0.96 (t, J=7 Hz,3H). MS calculated for C₁₅H₂₂BrNO+H: 312. observed: 312.

Example 11 (R,S)7-Hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(80 mg, 0.19 mmol) in dichloromethane (3 mL) was treated with BBr₃ (0.40mL of a 1.0M solution in CH₂Cl₂, 0.40 mmol) and stirred overnight at 20C. The excess BBr₃ was quenched with water and the product mixture wasdiluted with ether (20 mL), washed with Na₂CO₃ (10 mL) and brine (10mL), dried with Na₂SO₄ and concentrated. Flash chromatography (15% EtOAcin hexane, silica) resulted in 74 mg of a white solid. MS calculated forC₁₃H₁₃F₃INO₂+H: 400. observed: 400.

7-Hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(25 mg, 0.063 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20 C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 13 mg of a white solid. 1H NMR (400 MHz, CD₃OD) δ7.46 (s, 1H), 6.64 (s, 1H), 3.16 (m, 3H), 2.94 (m, 3H), 2.81 (m, 1H),1.35 (d, J=7 Hz, 3H). MS calculated for C₁₁H₁₄INO+H: 304. observed: 304.

Example 12 (R,S)7-Allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(30 mg, 0.075 mmol) in dichloromethane (2 mL) was treated with allylbromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hoursat 20 C. The product mixture was diluted with EtOAc (10 mL), washed with5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄ and concentrated.Flash chromatography (15% EtOAc in hexane, silica) resulted in 23 mg ofa clear oil. MS calculated for C₁₆H₁₇F₃INO₂+H: 440. observed: 440.

7-Allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(23 mg, 0.058 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20 C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 18 mg of a white solid. MS calculated forC₁₄H₁₈INO+H: 344. observed: 344.

Example 13 (R,S)3,5-Dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindeneo

N-trifluoroacetyl-3, 5-dimethyl-6, 7, 8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene

A solution ofN-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(158 mg, 0.360 mmol) in dimethylformamide (4 mL) was treated with KOAc(106 mg, 1.08 mmol), n-Bu₄NBr (116 mg, 0.360 mmol), PPh₃ (13 mg, 0.036mmol), Pd(OAc)₂ (4 mg, 0.018 mmol) and stirred overnight at 100 C. Theproduct mixture was filtered, water (10 mL) added and then extractedtwice with EtOAc (10 mL). The combined organic phases were washed withbrine (10 mL), dried with Na₂SO₄ and concentrated. Flash chromatography(5% EtOAc in hexane, silica) resulted in 15 mg of a clear oil. MScalculated for C₁₆H₁₆F₃NO₂+H: 312. observed: 312.

3,5-Dimethyl-6, 7, 8, 9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene

A solution ofN-trifluoroacetyl-3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene(15 mg, 0.048 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20 C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 10 mg of a white solid. 1H NMR (400 MHz, CDCl₃) δ7.25 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 3.12 (m, 1H), 2.97 (m, 4H),2.85 (m, 1H), 2.64 (bm, 1H), 2.15 (s, 3H), 1.34 (d, J=8 Hz, 3H). MScalculated for C₁₄H₁₇NO+H: 216. observed: 216.

Example 14 (R,S)7-Allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(48 mg, 0.15 mmol) in dichloromethane (2 mL) was treated with BBr₃ (0.30mL of a 1.0M solution in CH₂Cl₂, 0.30 mmol) and stirred overnight at 20C. The excess BBr₃ was quenched with water and the resulting mixturediluted with ether (20 mL), washed with Na₂CO₃ (10 mL) and brine (10mL), dried with Na₂SO₄ and concentrated. Flash chromatography (15% EtOAcin hexane, silica) resulted in 24 mg of a white solid. MS calculated forC₁₃H₁₃ClF₃NO₂+H: 308. observed: 308.

N-Trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(24 mg, 0.078 mmol) in dichloromethane (2 mL) was treated with allylbromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hoursat 20 C. The product mixture was diluted with EtOAc (10 mL), washed with5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄ and concentrated.Flash chromatography (15% EtOAc in hexane, silica) resulted in 23 mg ofa white solid. MS calculated for C₁₆H₁₇ClF₃NO₂+H: 348. observed: 348.

7-Allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(23 mg, 0.066 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20 C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 19 mg of a white solid. 1H NMR (400 MHz, CD₃OD) δ7.12 (s, 1H), 6.81 (s, 1H), 6.03 (m, 1H), 5.43 (d, J=17 Hz, 1H), 5.24(d, J=10 Hz, 1H), 4.57 (d, J=5 Hz, 2H), 3.1-2.9 (m, 5H), 2.81 (m, 1H),2.63 (m, 1H), 1.30 (d, J=7 Hz, 3H).

Example 15 (R,S)7-Methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-8-bromo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine(51 mg, 0.14 mmol) in 1,4-dioxane (2 mL) was treated withthiophene-2-boronic acid (36 mg, 0.28 mmol), K₂CO₃ (58 mg, 0.42 mmol),water (0.1 mL), Pd(PPh₃)₄ (16 mg, 0.014 mmol) and stirred overnight at100 C. The product mixture was diluted with EtOAc, filtered, absorbed onsilica and purified by flash chromatography (10% EtOAc in hexane,silica) resulting in 28 mg of a yellow solid. MS calculated forC₁₈H₁₈F₃NO₂S+H: 370. observed: 370.

7-Methoxy-1-methyl-8-(2-thienyl)-2, 3, 4, 5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(28 mg, 0.076 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred 0.5 hours at 50 C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 18 mg of a yellow oil. 1H NMR (400 MHz, CDCl₃) δ7.45 (d, J=4 Hz, 1H), 7.39 (s, 1H), 7.27 (d, J=6 Hz, 1H), 7.07 (dd, J=4,6 Hz, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 3.1-2.9 (m, 6H), 2.80 (m, 1H),2.22 (bs, 1H), 1.38 (d, J=7 Hz, 3H). MS calculated for C₁₆H₁₉NOS+H: 274.observed: 274.

Example 16 (R,S)8-Cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(18 mg, 0.05 mmol) in dimethylformamide (1 mL) was treated with CuCN (20mg, 0.24 mmol) and the mixture was microwaved at 200 C for 0.5 hours.The product mixture was diluted with water (5 mL), extracted twice withEtOAc (5 mL), the combined organic phases were washed with brine (5 mL),dried with Na₂SO₄ and concentrated. Flash chromatography (35% EtOAc inhexane, silica) resulted in 10 mg of a clear oil. MS calculated forC₁₅H₁₅F₃N₂O₂+H: 313. observed: 313.

8-Cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(10 mg, 0.032 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred 1 hour at 50 C. The product mixture was diluted withwater (5 mL), extracted twice with EtOAc (5 mL), the combined organicphases were washed with brine (5 mL), dried with Na₂SO₄ and concentratedto give 6.0 mg of a white solid. 1H NMR (400 MHz, CD₃OD) δ 7.33 (s, 1H),6.93 (s, 1H), 3.91 (s, 3H), 3.18-2.97 (m, 5H), 2.80 (m, 1H), 2.60 (m,1H), 1.33 (d, J=8 Hz, 3H). MS calculated for C₁₃H₁₆N₂O+H: 217. observed:217.

Example 17 (R,S)8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of diethyl zinc (1 mL, 1 M in hexanes) in dichloromethane (1mL) at 0 C was treated with trifluoroacetic acid in dichloromethane (0.5mL) and the mixture stirred for 15 min. Diiodomethane (0.280 g, 1.0mmol) in dichloromethane (0.5 mL) was then added and stirred for 15minutes.N-Trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine(0.075 g, 0.26 mmol) in dichloromethane (1 mL) was added and the mixturestirred for 30 minutes at 0 C and then for 2 hours at 20 C. The productmixture was quenched with aqueous saturated NH₄Cl (5 mL), extractedtwice with CH₂Cl₂ (20 mL), washed with saturated aqueous NaHCO₃ (10 mL),washed with H₂O (10 mL), and concentrated. Flash chromatography (7%EtOAc in hexanes, silica) resulted in 0.050 g of a white solid. MScalculated for C₁₅H₁₆F₃NO₂+H: 300. observed: 300.

N-Trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.025 g, 0.08 mmol) in acetonitrile (1 mL) was treated withN-bromosuccinimide (0.032 g, 0.18 mmol) and stirredfor 2 hrs. at 50 C.The product mixture was concentrated and then purified by flashchromatography (10% EtOAc in hexanes, silica) resulting in 0.014 g of awhite solid. MS calculated for C₁₅H₁₅BrF₃NO₂+H: 378. observed: 378.

8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,34,5-tetrahydro-1H-3-benzazepine(0.014 g, 0.037 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred for 2 hours at 50 C. The product mixture wasdiluted with brine (10 mL), extracted twice with EtOAc (10 mL), driedwith MgSO₄, and concentrated to give 0.008 g of a clear oil. 1H NMR (400MHz, CD₃OD) δ 7.26 (s, 1H), 6.78 (s, 1H), 3.83 (s, 3H), 3.02 (m, 2H),2.92 (m, 2H), 2.67 (s, 2H), 0.91 (m, 2H), 0.85 (m, 2H). MS calculatedfor C₁₃H₁₆BrNO+H: 282. observed: 282.

Example 18 (R,S)8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine(0.100 g, 0.35 mmol) in tetrahydrofuran (1 mL) was treated with BH₃-THFcomplex (0.36 mL, 1 M in THF), and stirred for 30 min. at 20 C. Water(0.5 mL), saturated aqueous NaHCO₃ (0.5 mL), and 30% H₂O₂ (0.2 mL) wereadded sequentially and the reaction stirred for 30 min. at 20 C. Theproduct mixture was diluted with EtOAc (10 mL), washed with brine (10mL), and concentrated. Flash chromatography (33% EtOAc in hexane,silica) resulted in 0.035 g of a clear oil. MS calculated forC₁₄H₁₆F₃NO₃+H: 304. observed: 304.

N-Trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.035 g, 0.12 mmol) in acetonitrile (1 mL) was treated withN-bromosuccinimide (0.025 g, 0.14 mmol), and stirred for 30 min. at 20C. The product mixture was concentrated and then purified by flashchromatography (33% EtOAc in hexane, silica) resulting in 0.019 g clearoil. MS calculated for C₁₄H₁₅BrF₃NO₃+H: 382. observed: 382.

8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.009 g, 0.024 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred for 1 hour at 50 C. The product mixture wasdiluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried withMgSO₄, and concentrated to give 0.006 g clear oil. 1H NMR (400 MHz,CD₃OD) δ 7.28 (s, 1H), 6.79 (s, 1H), 3.84 (m, 2H), 3.0-2.8 (m, 7H). MScalculated for C₁₂H₁₆BrNO₂+H: 286. observed: 286.

Example 19 (R,S)8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Crotyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (6.68 g,17.9 mmol) in toluene (100 mL) was treated with K₂CO₃ (3.22 g, 23.3mmol), KOH (3.01 g, 53.7 mmol), n-Bu₄NBr (0.580 g, 1.80 mmol) and crotylbromide (3.15 g, 23.3 mmol). The mixture was stirred at 75 C for 16hours, cooled to 20 C, diluted with Et₂O (500 mL), washed with 10%aqueous HCl (500 mL) and concentrated. Flash chromatography (10% EtOAcin hexane, silica) resulted in 5.22 g of a clear oil. MS calculated forC₁₅H₁₇F₃INO₂+H: 428. observed: 428.

N-Trifluoroacetyl-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-crotyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine(5.20 g, 12.2 mmol) in dimethylformamide (80 mL) was treated with KOAc(3.59 g, 36.6 mmol), n-Bu₄NBr (3.93 g, 12.2 mmol), PPh₃ (0.320 g, 1.22mmol), Pd(OAc)₂ (0.137 g, 0.61 mmol) and stirred overnight at 90 C. Theproduct mixture was cooled to 20 C, diluted with water (200 mL),extracted twice with ether (500 mL), the combined organic phases washedtwice with brine (200 mL), and concentrated. Flash chromatography (10%EtOAc in hexane, silica) resulted in 2.29 g of a clear oil, whichconsists of a mixture of olefinic isomers. MS calculated forC₁₅H₁₆F₃NO₂+H: 300. observed: 300.

N-Trifluoroacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(2.29 g, 7.65 mmol) in methanol (100 mL) was treated with 10% Pd/C (4.0g, 0.77 mmol)) and stirred overnight under an atmosphere of hydrogen.The product mixture was filtered through a pad of celite and silica, andthe solvent removed to give 2.14 g of a clear oil. MS calculated forC₁₅H₁₈F₃NO₂+H: 302. observed: 302.

N-Trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.710 g, 2.36 mmol) in acetonitrile (20 mL) was treated withN-bromosuccinimide (0.504 g, 2.83 mmol), and stirred overnight at 20 C.The product mixture was concentrated, diluted with EtOAc (100 mL),washed with water (50 mL) and brine (50 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (10% EtOAc in hexanes, silica)resulted in 0.561 g of a clear oil. MS calculated for C₁₅H₁₇BrF₃NO₂+H:380. observed: 380.

8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.561 g, 1.48 mmol) in methanol (30 mL) was treated with 15% aqueousNaOH (30 mL), and stirred overnight at 20 C. The product mixture wasdiluted with brine (100 mL), extracted twice with EtOAc (200 mL), driedwith MgSO₄, and concentrated to give 0.412 g of a clear oil. 1H NMR (400MHz, CD₃OD) δ 7.24 (s, 1H), 6.76 (s, 1H), 3.83 (s, 3H), 3.02 (m, 3H),2.91 (s, 1H), 2.85-2.76 (m, 3H), 2.63 (m, 1H), 1.78 (m, 1H), 1.72 (m,1H), 0.94 (dd, J=8, 8 Hz, 3H). MS calculated for C₁₃H₁₈BrNO+H: 284.observed: 284.

Example 20 (R,S)8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.600 g, 1.99 mmol) in acetonitrile (20 mL) was treated withN-chlorosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 60 C.The product mixture was concentrated, diluted with EtOAc (100 mL),washed with water (50 mL) and brine (50 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (10% EtOAc in hexanes, silica)resulted in 0.421 g of a clear oil. MS calculated for C₁₅H₁₇ClF₃NO₂+H:336. observed: 336.

8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.421 g, 1.25 mmol) in methanol (30 mL) was treated with 15% aqueousNaOH (30 mL), and stirred overnight at 20 C. The product mixture wasdiluted with brine (100 mL), extracted twice with EtOAc (200 mL), driedwith MgSO₄, and concentrated to give 0.241 g of a clear oil. 1H NMR (400MHz, CD₃OD) d 7.05 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.03 (m, 3H),2.91 (s, 1H), 2.86-2.76 (m, 3H), 2.64 (m, 1H), 1.81 (m, 1H), 1.72 (m,1H), 0.93 (dd, J=8, 8 Hz, 3H). MS calculated for C₃H₁₈cINO+H: 240.observed: 240.

Example 21 (R,S)8-Bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-(3-methylbut-2-enyl), N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (0.700 g,1.88 mmol) in toluene (25 mL) was treated with K₂CO₃ (0.340 g, 2.4mmol), KOH (0.210 g, 3.76 mmol), n-Bu₄NBr (0.060 g, 0.19 mmol) and4-bromo-2-methyl-2-butene (0.364 g, 2.44 mmol). The mixture was stirredat 80 C for 3 hours, cooled to 20 C, diluted with ether (100 mL), washedwith 10% HCl (50 mL) and concentrated; Flash chromatography (10% EtOAcin hexane, silica) resulted in 0.272 g of a clear oil. 1H NMR (400 MHz,CDCl₃, mixture of rotamers) d 7.65 (m, 1H), 6.75 (m, 1H), 6.54 (m, 1H),5.20 (m, 0.4H), 5.0 (m, 0.6H), 4.10 (m, 1H), 3.82 (m, 1H), 3.76 (d, 2H),3.50 (m, 2H), 3.02 (m, 2H), 1.75 (m, 3H), 1.66 (m, 3H).

N-Trifluoroacetyl-1-isopropylene-7-methoxy-2,3, 4,5-tetrahydro-1H-3-benzazepine

A solution of N-(3-methylbut-2-enyl),N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (0.0272 g, 0.62 mmol)in dimethylformamide (12 mL) was treated with KOAc (0.183 g, 1.86 mmol),n-Bu₄NBr (0.200 g, 0.062 mmol), PPh₃ (0.016 g, 0.062 mmol), Pd(OAc)₂(0.183 g, 1.86 mmol) and stirred overnight at 90 C. The product mixturewas cooled to 20 C, diluted with water (50 mL), extracted twice withether (50 mL), the combined organic phases were washed with brine (50mL), and concentrated. Flash chromatography (10% EtOAc in hexane,silica) resulted in 0.096 g of a clear oil. MS calculated forC₁₆H₁₈F₃NO₂+H: 314. observed: 314.

N-Trifluoroacetyl-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-1-isopropylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.096 g, 0.31 mmol) in ethanol (2 mL) was treated with 10% Pd/C (0.033g, 0.031 mmol)) and stirred overnight under an atmosphere of hydrogen.The product mixture was filtered through a pad of celite and silica, andthe solvent removed to give 0.091 g of a clear oil. MS calculated forC₁₆H₂₀F₃NO₂+H: 316. observed: 316.

N-Trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluorolacetyl-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.091 g, 0.29 mmol) in acetonitrile (3 mL) was treated withN-bromosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 20 C.After removing the solvent, flash chromatography (10% EtOAc in hexanes,silica) resulted in 0.056 g of a clear oil. MS calculated forC₁₆H₁₉BrF₃NO₂+H: 394. observed: 394.

8-Bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.013 g, 0.03 mmol) methanol (0.5 mL) was treated with 15% aqueous NaOH(0.5 mL), and stirred overnight at 20 C. The product mixture was dilutedwith brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO₄,and concentrated to give 0.10 g of a clear oil. 1H NMR (400 MHz, CD₃OD)δ 7.08 (s, 1H), 6.64 (s, 1H), 3.72 (s, 3H), 3.2-3.10 (m, 3H), 2.7-2.5(m, 3H), 2.3-2.1 (m, 2H), 0.96 (d, 3H), 0.63 (d, 3H). MS calculated forC₁₄H₂₀BrNO+H: 298. observed: 298.

Example 22 (R,S)8-Bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.041 g, 0.10 mmol) in dichloromethane (1 mL) was treated with BBr₃(0.32 ml, 1.0 M solution in CH₂Cl₂) and stirred overnight at 20 C. Theexcess BBr₃ is quenched with water and the resulting mixture dilutedwith ether (50 mL), washed twice with saturated aqueous Na₂CO₃ (20 mL)and concentrated. Flash chromatography (20% EtOAc in hexanes, silica)resulted in 0.037 g clear oil. MS calculated for C₁₅H₁₇BrF₃NO₂+H: 380.observed: 380.

8-Bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.018 g, 0.047 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred for 3 hours at 50 C. The product mixture 1 towas brought to pH 7-8 with 10% aqueous HCl, extracted three times withEtOAc (50 mL), dried with MgSO₄, and concentrated to give 0.013 g of awhite solid. 1H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 6.60 (s, 1H), 3.30(m, 1H), 3.2-3.0 (m, 2H), 2.78 (m, 1H), 2.7-2.5 (m, 2H), 2.3-2.1 (m,2H), 1.05 (d, 3H), 0.73 (d, 3H). MS calculated for C₁₃H₁₈BrNO+H: 284.observed: 284.

Example 23 (R,S)7-Allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated withN′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3hours at 20 C. The product mixture was diluted with 10% aqueous HCl,extracted twice with dichloromethane (20 mL), and concentrated. Flashchromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of aclear oil. MS calculated for C₁₈H₂₁BrF₃NO₂+H: 420. observed: 420.

7-Allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.011 g, 0.026 mmol) in methanol (0.5 mL) was treated with of 15%aqueous NaOH (0.5 mL), and stirred for 3 hours at 50 C. The productmixture was diluted with brine (5 mL), extracted twice with EtOAc (5mL), dried with MgSO₄, and concentrated to give 0.010 g of a clear oil.1H NMR (400 MHz, CD₃OD) δ 7.09 (s, 1H), 6.62 (s, 1H), 5.94 (m, 1H), 5.32(dd, 1H), 5.12 (dd, 1H), 4.46 (d, 2H), 3.19 (m, 1H), 3.05 (m, 2H), 2.66(m, 1H), 2.5 (bm, 2H), 2.3-2.1 (m, 2H), 0.95 (d, 3H), 0.63 (d, 3H). MScalculated for C₁₆H₂₂BrNO+H: 324. observed: 324.

Example 248-Bromo-7-methoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-1-(3-methoxyphenyl)-2-propylamine

A solution of 1-(3-methoxyphenyl)-2-propylamine (3.59 g, 21.7 mmol) indichloromethane (75 mL) at 0 C, was treated with pyridine (2.1 mL, 28.2mmol), trifluoracetic anhydride (5.9 g, 28.2 mmol), and then stirred for3 hours while warming 15 to 20 C. The product mixture was diluted withEtOAc (300 mL), washed sequentially with 10% aqueous HCl (100 mL), water(100 mL), brine (100 mL), dried with Na₂SO₄ and concentrated. Flashchromatography (20% EtOAc in hexane, silica) resulted in 4.29 g of ayellow solid. 1H NMR (400 MHz, CD₃OD) d 7.17 (dd, J=8, 8 Hz, 1H), 6.76(m, 3H), 4.19 (m, 1H), 3.77 (s, 3H), 2.78 (m, 2H), 1.21 (d, J=7 Hz, 2H).

N-Trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine

A solution of N-trifluoroacetyl-1-(3-methoxyphenyl)-2-propylamine (4.29g, 15.7 mmol) in methanol (100 mL) was cooled to −78 C and treated withCaCO₃ (3.17 g, 31.4 mmol), followed by a solution of ICl (6.37 g, 39.3mmol) in methanol (50 mL). The reaction was allowed to warm to 20 Cwhile stirring overnight. The product mixture was filtered,concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueoussodium bisulfite (100 mL), once with brine (100 mL), dried with Na₂SO₄and concentrated to give 6.72 g of a white solid powder. MS calculatedfor C₁₂H₁₃F₃INO₂+H: 388. observed: 388.

N-Allyl, N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine

A solution of N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine(6.09 g, 15.7 mmol) in toluene (450 mL) was treated with K₂CO₃ (2.82 g,20.4 mmol), KOH (2.45 g, 47.1 mmol), n-Bu₄NBr (0.506 g, 1.57 mmol) andallyl bromide (2.47 g, 20.4 mmol), and stirred overnight at 80 C. Theproduct mixture was acidified with 10% aqueous HCl, separated, theaqueous phase extracted with ether (500 mL), the combined organic phaseswere washed with brine (200 mL), dried with Na₂SO₄ and concentrated togive 4.45 g of a brown oil.

N-Trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-allyl,N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine (4.45 g, 10.8mmol) in dimethylformamide (120 mL) was treated with KOAc (3.17 g, 32.3mmol), n-Bu₄NBr (3.47 g, 10.8 mmol), PPh₃ (0.283 g, 1.08 mmol), Pd(OAc)₂(0.242 g, 1.08 mmol) and stirred overnight at 80 C. The product mixturewas cooled to 20 C, filtered, diluted with water (200 mL), extractedwith ether (3×200 mL), the combined organic phases washed with water(100 mL), brine (100 mL), dried with Na₂SO₄ and concentrated. Flashchromatography (10% EtOAc in hexane, silica) resulted in 1.39 g of ayellow oil.

N-Trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine(1.39 g, 4.64 mmol) in ethanol (40 mL) was treated with 10% Pd/C (0.49g, 0.46 mmol) and stirred overnight under an atmosphere of hydrogen. Theproduct mixture was filtered through a pad of celite and silica and thenconcentrated. Flash chromatography (20% EtOAc in hexane, silica)resulted in 0.77 g of a clear oil. 1H NMR (400 MHz, CDCl₃, mixture ofrotamers) d 7.06 (m, 1H), 6.71 (m, 1H), 6.63 (m, 1H), 4.38 (bm, 1H), 3.8(s, 3H), 3.6 (m, 1H), 3.25 (m, 1H), 3.18 (bm, 2H), 2.72 (m, 1H), 1.34(m, 3H) 1.22 (m, 3H).

N-Trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solutionN-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated withN-bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 C.The product mixture was diluted with EtOAc (100 mL), washed with sodiumbisulfite (50 mL) and brine (50 mL), dried with Na₂SO₄ and concentrated.Flash chromatography (20% EtOAc in hexane, silica) resulted in a clearoil. 1H NMR (400 MHz, CDCl₃, mixture of rotamers) d 7.32 (s, 1H), 6.62(m, 1H), 4.37 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H), 3.28-3.10 (m, 3H),2.73 (m, 1H), 1.31 (m, 3H), 1.25 (m, 3H).

8-Bromo-1, 4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(21 mg, 0.055 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20 C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (10 mL), the combinedorganic phases were washed with brine (10 mL), dried with Na₂SO₄ andconcentrated to give 11 mg of a clear oil. 1H NMR (400 MHz, CDCl₃) δ7.29 (s, 1H), 6.64 (s, 1H), 3.88 (s, 3H), 3.02 (m, 2H), 2.89 (dd, J=9,14 Hz, 1H), 2.80 (m, 1H), 2.67 (d, J=14 Hz, 1H), 2.53 (dd, J=10, 13, 1H) 1.30 (d, J=7 Hz, 3H), 1.19 (d, J=6 Hz, 3H). MS calculated forC₁₃H₁₈BrNO+H: 284. observed: 284.

Example 257-Allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.383 g, 1.01 mmol) in dichloromethane (30 mL) was treated with BBr₃(2.35 mL of a 1.0M solution in CH₂Cl₂, 2.35 mmol) and stirred overnightwhile warming to 20 C. The excess BBr₃ is quenched with water, and theresulting mixture was diluted with ether (100 mL), washed with saturatedaqueous Na₂CO₃ (50 mL) and brine (50 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.302 g of a white solid. 1H NMR (400 MHz, CDCl₃, mixture ofrotamers) d 7.22 (m, 1H), 6.77 (m, 1H), 5.34 (s, 1H), 4.35 (m, 1H), 3.62(m, 1H), 3.24 (m, 1H), 3.13 (m, 2H), 2.69 (m, 1H), 1.31 (m, 3 H), 1.22(m, 3H).

N-Trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solutionN-trifluoroacetyl-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.030 g, 0.082 mmol) in dichloromethane (2 mL) was treated with allylbromide (0.030 g, 0.246 mmol), DBU (0.037 g, 0.246 mmol) and stirred 2hours at 20 C. The product mixture was diluted with EtOAc (10 mL),washed with 5% aqueous HCl (2 mL), brine (5 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.028 g of a clear oil. 1H NMR (400 MHz, CDCl₃, mixture ofrotamers) d 7.32 (s, 1H), 6.62 (m, 1H), 6.02 (m, 1H), 5.45 (d, J=17 Hz,1H), 5.30 (d, J=11 Hz, 1H), 4.58 (s, 2H), 4.36 (m, 1H), 3.62 (m, 1H),3.23 (m, 1H), 3.11 (m, 1H), 2.81 (d, J=10 Hz, 1H), 2.70 (m, 1H), 1.34(m, 3H), 1.21 (m, 3H).

7-Allyloxy-8-bromo-1, 4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.028 g, 0.069 mmol) in methanol (2 mL) was treated with 15% aqueousNaOH (2 mL), and stirred for 3 hours at 20 C. The product mixture wasdiluted with water (10 mL), extracted twice with EtOAc (10 mL), thecombined organic phases were washed with brine (10 mL), dried withNa₂SO₄ and concentrated to give 0.020 g of a clear oil. 1H NMR (400 MHz,CDCl₃) δ 7.30 (s, 1H), 6.64 (s, 1H), 6.06 (m, 1H), 5.47 (d, J=17 Hz,1H), 5.30 (d, J=11 Hz, 1H), 4.56 (s, 2H), 3.03 (m, 2H), 2.90 (dd, J=9,14 Hz, 1H), 2.80 (m, 1H), 2.65 (d, J=14 Hz, 1H), 2.55 (dd, J=10, 14 Hz,1H), 1.77 (bs, 1H), 1.30 (d, J=7 Hz, 3H), 1.20 (d, J=6 Hz, 3H).

Example 26 (R,S) 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-4-chlorophenethylamine

A solution of 4-chlorophenethylamine (1.0 g, 6.4 mmol) indichloromethane (20 mL) was cooled to 0 C, treated with pyridine (1.0mL, 12.8 mmol), trifluoracetic anhydride (1.6 g, 7.7 mmol) and thenstirred for 1 hour while warming to 20 C. The product mixture wasdiluted with EtOAc (100 mL), washed sequentially with 10% aqueous HCl(50 mL), water (50 mL), brine (50 mL), dried with Na₂SO₄ andconcentrated to give 1.6 g of a white solid.

N-Trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-4-chlorophenethylamine (1.6 g, 6.4 mmol)in dichloromethane (20 mL) was treated withbis(pyridine)iodonium(I)tetrafluoroborate (2.6 g, 7.0 mmol), CF₃SO₃H(2.1 g, 14.1 mmol) and stirred overnight at 20 C. The product mixturewas concentrated, dissolved in EtOAc (100 mL), washed twice with 5%aqueous sodium bisulfite (50 mL), twice with saturated aqueous NaHCO₃,(50 mL) once with brine (50 mL), dried with Na₂SO₄ and concentrated togive 0.94 g of a clear oil. MS calculated for C₁₀H₈ClF₃INO+H: 378.observed: 378.

N-Allyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (0.94 g,2.4 mmol) in toluene (25 mL) was treated with K₂CO₃ (0.43 g, 3.12 mmol),KOH (0.40 g, 7.2 mmol), n-Bu₄NBr (0.077 g, 0.24 mmol) and allyl bromide(0.43 g, 3.6 mmol) sequentially. The mixture was stirred at 80 C for 3.5hours, cooled to 20 C and acidified with 10% aqueous HCl. The phaseswere separated, the aqueous phase extracted with ether (100 mL), thecombined organic phases were washed with brine (50 mL), dried withNa₂SO₄ and concentrated to give 0.76 g of a clear oil. MS calculated forC₁₃H₁₂ClF₃INO+H: 418. observed: 418.

N-Trifluoroacetyl-8-chloro-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-allyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine(0.76 g, 1.8 mmol) in dimethylformamide (20 mL) was treated with KOAc(0.53 g, 5.4 mmol), n-Bu₄NBr (0.58 g, 1.8 mmol), PPh₃ (0.047 g, 0.18mmol), Pd(OAc)₂ (0.041 g, 0.18 mmol) and stirred overnight at 105 C. Theproduct mixture was cooled to 20 C, filtered, diluted with water (100mL), extracted with ether (3×100 mL), the combined organic phases washedwith water (100 mL), brine (100 mL), dried with Na₂SO₄ and concentrated.Flash chromatography (10% EtOAc in hexane, silica) resulted in 0.228 gof a clear oil. 1H NMR (400 MHz, CDCl₃) d 7.29 (s, 1H), 7.18 (m, 1H),7.04 (m, 1H), 5.38 (m, 2H), 5.40 (d, J=16 Hz, 2H), 3.80 (m, 2H), 3.00(m, 2H). MS calculated for C₁₃H₁₁ClF₃NO+H: 290. observed: 290.

N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methylene-2,3,4,5-trihydro-1H-3-benzazepine(0.16 g, 0.55 mmol) in methanol (10 mL) was treated with 10% Pd/C (0.02g) and stirred 30 minutes under an atmosphere of hydrogen. The productmixture was filtered, concentrated and purified by flash chromatography(5% EtOAc in hexane, silica) resulting in 0.057 g of a white solid. MScalculated for C₁₃H₁₃ClF₃NO+H: 292. observed: 292.

8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(65 mg, 0.22 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 60 C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, CDCl₃) δ7.11 (s, 1H), 7.05 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 3.1-2.9 (m,6H), 2.71 (m, 1H), 2.68 (bs, 1H), 1.32 (d, J=8 Hz, 3H). MS calculatedfor C₁₁H₁₄ClN+H: 196. observed: 196.

Example 27 (R,S)7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.506 g, 1.76 mmol) in dichloromethane (20 mL) was treated with BBr₃(4.1 mL of a 1.0M solution in CH₂Cl₂, 4.1 mmol) and stirred overnightwhile warming to 20 C. The excess BBr₃ was quenched with water, and theresulting mixture was diluted with ether (200 mL), washed with Na₂CO₃(100 mL) and brine (100 mL), dried with Na₂SO₄ and concentrated. Flashchromatography (15% EtOAc in hexane, silica) resulted in 0.460 g of awhite solid foam. MS calculated for C₁₃H₁₄F₃NO₂+H: 274. observed: 274.

N-Trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate

A solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(460 mg, 1.76 mmol) in dichloromethane (15 mL) was treated with pyridine(417 mg, 5.27 mmol), trifluoromethanesulfonic anhydride (991 mg, 3.52mmol) and stirred 1.5 hours at 20 C. The product mixture was dilutedwith dichloromethane (100 mL), washed with water (50 mL), 5% aqueous HCl(50 mL), saturated aqueous NaHCO₃ (50 mL), brine (50 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (15% EtOAc in hexane,silica) resulted in 658 mg of a clear oil. MS calculated forC₁₄H₁₃F₆NO₄S+H: 406. observed: 406.

N-Trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate (100 mg, 0.25 mmol) in dimethylformamide (2mL) was treated with (2-methyl-2H-pyrazol-3-yl)-tri-n-butyltin (138 mg,0.37 mmol), LiCl (21 mg, 0.50 mmol), Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol) andstirred at 100 C for 4 hours. The product mixture was diluted with EtOAc(20 mL), washed twice with water (10 mL), once with brine (10 mL), driedwith Na₂SO₄ and concentrated. Flash chromatography (30% EtOAc in hexane,silica) resulted in 80 mg of a clear oil. MS calculated forC₁₇H₁₈F₃N₃O+H: 338. observed: 338.

7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(48 mg, 0.14 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and the solution stirred overnight at 20 C. The product mixturewas concentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried withNa₂SO₄ and the solvent evaporated. Flash chromatography (0-15% MeOH inCH₂Cl₂, silica) resulted in 30 mg of a clear oil. 1H NMR (400 MHz,CDCl₃) δ 7.48 (s, 1H), 7.21 (m, 2H), 7.13 (s, 1H), 6.27 (s, 1H), 3.89(s, 3H), 3.3-2.9 (m, 9H), 2.79 (dd, J=7, 14 Hz, 1H), 1.40 (d, J=8 Hz,3H). MS calculated for C₁₅H₁₉N₃+H: 242. observed: 242.

Example 28 (R,S)7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-(4-bromo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a solution ofN-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(30 mg, 0.082 mmol) in dichloromethane (1 mL) was treated withN-bromosuccinimide (15.3 mg, 0.086 mmol) and stirred overnight at 20 C.The product mixture was absorbed on silica and purified by flashchromatography (2-5% MeOH in CH₂Cl₂, silica) resulting in 37 mg of awhite crystalline solid. MS calculated for C₁₇H₁₇BrF₃N₃O+H: 416.observed: 416.

7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-(4-bromo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(37 mg, 0.089 mmol) in methanol (2 mL) was treated with of 15% aqueousNaOH (2 mL), and stirred overnight at 20 C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and the solvent evaporated. Flash chromatography (0-15% MeOH in CH₂Cl₂,silica) resulted in 28 mg of a clear oil. 1H NMR (400 MHz, CDCl₃) δ 7.50(s, 1H), 7.25 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.10 (s, 1H), 3.83(s, 3H), 3.17 (m, 1H), 3.1-2.9 (m, 8H), 2.80 (dd, J=7, 13 Hz, 1H), 2.48(bs, 1H), 1.40 (d, J=8 Hz, 3H). MS calculated for C₁₅H₁₈BrN₃+H: 320.observed: 320.

Example 29 (R,S)7-(3-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate (50 mg, 0.123 mmol) in 1,4-dioxane (1.5 mL)was treated with 2-chlorophenylboronic acid (39 mg, 0.243 mmol), CsF (56mg, 0.37 mmol), water (50 mg, 2.78 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol)and stirred overnight at 75 C. The product mixture was diluted withEtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (10-20% EtOAc in hexane,silica) resulted in 45 mg of a clear oil. MS calculated forC₁₉H₁₇ClF₃NO+H: 368. observed: 368. The product (27 mg, 0.073 mmol) wasdissolved in methanol (2 mL) treated with 15% aqueous NaOH (2 mL), andstirred overnight at 20 C. The product mixture was concentrated,extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄ and the solventevaporated to give 18 mg of a clear oil. 1H NMR (400 MHz, CDCl₃) δ 7.54(s, 1H), 7.42 (d, J=6 Hz, 1H), 7.35-7.21 (m, 5H), 3.14 (m, 1H), 3.1-2.9(m, 8H), 2.80 (bm, 2H), 1.38 (d, J=8 Hz, 3H). MS calculated forC₁₇H₁₈ClN₃+H: 272. observed: 272.

Example 30 (R,S)7-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate (50 mg, 0.123 mmol) in 1,4-dioxane (1.5 mL)was treated with 2-chlorophenylboronic acid (39 mg, 0.243 mmol), CsF (56mg, 0.37 mmol), water (50 mg, 2.78 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol)and stirred overnight at 75 C. The product mixture was diluted withEtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (10-20% EtOAc in hexane,silica) resulted in 36 mg of a clear oil. MS calculated forC₁₉H₁₇ClF₃NO+H: 368. observed: 368. The product (27 mg, 0.073 mmol) wasdissolved in methanol (2 mL) treated with 15% aqueous NaOH (2 mL), andstirred overnight at 20 C. The product mixture was concentrated,extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄ and the solventevaporated to give 24 mg of a clear oil. 1H NMR (400 MHz, CDCl₃) d 7.44(d, J=8 Hz, 1H), 7.35-7.22 (m, 5H), 7.15 (s, 1H), 3.14 (m, 1H), 3.1-2.9(m, 8H), 2.80 (dd, J=13, Hz, 1H), 2.51 (bs, 1H), 1.38 (d, J=8 Hz, 3 H).MS calculated for C₁₇H₁₈ClN₃+H: 272. observed: 272.

Example 31 (R,S) 8-Chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-1-oxo-,3,4,5-trihydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methylene-3,4,5-trihydro-H-3-benzazepine(0.23 g, 0.80 mmol) in 1:1 methanol/dichloromethane (45 mL) was cooledto −78 C, treated with ozone until the solution turned blue (about 20minutes), PPh₃ (0.21 g, 0.80 mmol) was added and the resulting solutionwas stirred 90 minutes while 1 to warming to 20 C. The product mixturewas concentrated and purified by flash chromatography (30% EtOAc inhexane, silica) resulting in 0.215 g of a white solid. MS calculated forC₁₂H₉ClF₃NO₂+H: 292. observed: 292.

8-Chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-oxo-3,4,5-trihydro-1H-3-benzazepine (50 mg,0.17 mmol) in methanol (2 mL) was treated with NaBH₄ and the resultingmixture was stirred 16 hours at 20 C. The white solid product wascollected by filtration, washed with water and dried, resulting in 30 mgof a white solid. 1H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 7.12 (d, J=8Hz, 1H), 7.06 (d, J=8 Hz, 1H), 4.74 (d, J=8 Hz, 1H), 3.1-2.7 (m, 6H). MScalculated for C₁₀H₁₂ClNO+H: 198. observed: 198.

Example 32 (R,S) 8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26, (R,S)8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained from4-bromophenethylamine as a colorless oil. 1H NMR (400 MHz, CDCl₃) δ 7.27(s, 1H), 7.22 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 3.1-2.85 (m, 6H),2.72 (m, 1H), 2.25 (bs, 1H), 1.33 (d, J=7 Hz, 3H). MS calculated forC₁₁H₁₄BrN+H: 240. observed: 240.

Example 33 (R,S) 8-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26, (R,S)8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained from4-fluorophenethylamine as a colorless oil. 1H NMR (400 MHz, CDCl₃) δ7.00 (dd, J=8, 10 Hz, 1H), 6.86 (d, J=10 Hz, 1H), 6.76 (d, J=8 Hz, 1H),3.08-2.56 (m, 7H), 1.85 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MS calculatedfor C₁₁H₁₄FN+H: 180. observed: 180.

Example 34 (R,S) 7-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26, (R,S)7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained from3-fluorophenethylamine as a colorless oil. 1H NMR (400 MHz, CDCl₃) δ7.09 (dd, J=6, 8 Hz, 1H), 6.85-6.78 (m, 2H), 3.10-2.89 (m, 6H), 2.71(dd, J=7, 13 Hz, 1H), 1.91 (bs, 1H), 1.33 (d, J=7 Hz, 3H). MS calculatedfor C₁₁H₁₄FN+H: 180. observed: 180.

Example 35 (R,S) 7-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26, (R,S)7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained from3-chlorophenethylamine as a colorless oil. 1H NMR (400 MHz, CDCl₃) δ7.10 (d, J=8 Hz, 1H), 7.06 (m, 2H), 3.1-2.9 (m, 6H), 2.70 (dd, J=13, 7Hz, 1H), 1.89 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated forC₁₁H₁₄ClN+H: 196. observed: 196.

Example 36 (R,S)7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26, (R,S)7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtainedfrom 3,4-dichlorophenethylamine as a colorless oil. 1H NMR (400 MHz,CDCl₃) δ 7.20 (s, 1H), 7.16 (s, 1H), 3.05-2.86 (m, 6H), 2.71 (dd, J=7,13 Hz, 1H), 1.83 (bs, 1H), 1.33 (d, J=7 Hz, 3H). MS calculated forC₁₁H₁₃Cl₂N+H: 230. observed: 230.

Example 37 (R,S)N-Methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 9, (R,S)N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from (R,S)8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a colorlessoil. MS calculated for C₁₂H₁₆ClN+H: 210. observed: 210.

Example 38 (R,S)1-Methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26, (R,S)I-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from 3-trifluoromethoxyphenethylamine as a colorless oil. 1HNMR (400 MHz, CD₃OD) 7.39 (d, J=8 Hz, 1H), 7.19 (m, 1H), 3.46 (m, 2H),3.38 (d, J=13 Hz, 1H), 3.29 (m, 1H), 3.16 (m, 2H), 3.05 (dd, J=13, 9 Hz,1H), 1.50 (d, J=8 Hz, 3H). MS calculated for C₁₂H₁₄F₃NO+H: 246.observed: 246.

Example 39 (R,S)8-Iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 3, (R,S)8-iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepineas a colorless oil. 1H NMR (400 MHz, CD₃OD) d 7.79 (s, 1H), 7.25 (s,1H), 3.46-3.40 (m, 3H), 3.28-3.12 (m, 3H), 3.07 (dd, J=13, 9 Hz, 1H),1.47 (d, J=7 Hz, 3H). MS calculated for C₁₂H₁₄F₃INO+H: 372. observed:372.

Example 40 (R,S)N-Propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 10, (R,S)N-Propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained from (R,S)8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine as acolorless oil. MS calculated for C₁₅H₂₂INO+H: 360. observed: 360.

Example 41 (R,S)1-Ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 19, (R,S)1-ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained fromN-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepineas a colorless oil. 1H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 6.54 (s,1H), 3.86 (s, 3H), 3.20-2.97 (m, 4H), 2.93-2.75 (m, 3H), 2.64 (m, 1H),1.78 (m, 2H), 0.95 (dd, J=8, 8 Hz, 3H). MS calculated for C₁₃H₁₈NO+H:332. observed: 332.

Example 42 (R,S)7-(3-Methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29, (R,S)7-(3-Methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. 1H NMR (400 MHz, CDCl₃)δ 7.37 (dd, J=7, 7 Hz, 1H), 7.30 (m, 2H), 7.21 (d, J=7 Hz, 1H), 7.14 (d,J=7 Hz, 1H), 7.09 (s, 1H), 6.86 (d, J=8 Hz, 1H), 3.85 (s, 3H), 3.2-2.9(m, 6H), 2.80 (m, 1H), 2.64 (bs, 1H), 1.38 (d, J=7 Hz, 3H). MScalculated for C₁₈H₂₁NO+H: 268. observed: 268.

Example 43 (R,S)7-(2,6-difluorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29, (R,S)7-(2,6-difluorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. 1H NMR (400 MHz, CDCl₃)δ 7.35-7.10 (m, 5H), 6.95 (dd, J=7, 8 Hz, 1H), 3.2-2.9 (m, 6H), 2.79(dd, J=8, 13 Hz, 1H), 2.70 (bs, 1H), 1.38 (d, J=8 Hz, 3H). MS calculatedfor C₁₇H₁₇F₂N+H: 274. observed: 274.

Example 44 (R,S)7-(2-fluorophenyl)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29, (R,S)7-(2-fluorophenyl)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineas a colorless oil. 1H NMR (400 MHz, CDCl₃) δ 7.35-7.23 (m, 3H),7.19-7.09 (m, 2H), 7.03 (s, 1H), 3.15-2.85 (m, 7H), 2.76 (dd, J=8, 13Hz, 1H), 1.36 (d, J=8 Hz, 3H). MS calculated for C₁₇H₁₇ClFN+H: 290.observed: 290.

Example 45 (R,S)7-(2-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29, (R,S)7-(2-trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. 1H NMR (400 MHz, CDCl₃)δ 7.71 (d, J=8 Hz, 1H), 7.52 (dd, J=7, 8 Hz, 1H), 7.42 (dd, J=7, 8 Hz,1H), 7.31 (d, J=7 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H),3.15 (m, 1H), 3.1-2.9 (m, 5H), 2.76 (dd, J=8, 13 Hz, 1H), 2.37 (bs, 1H),1.38 (d, J=8 Hz, 3H). MS calculated for C₁₈H₁₈F₃N+H: 306. observed: 306.

Example 46 (R,S)7-(3-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29, (R,S)7-(3-trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. 1H NMR (400 MHz, CDCl₃)δ 7.80 (s, 1H), 7.73 (d, J=8 Hz, 1H), 7.57-7.48 (m, 2H), 7.38 (d, J=8Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=7 Hz, 1H), 3.16 (m, 1H), 3.1-2.9 (m,6H), 2.79 (dd, J=8, 13 Hz, 1H), 1.38 (d, J=8 Hz, 3H). MS calculated forC₁₈H₁₈F₃N+H: 306. observed: 306.

Example 47 (R,S)7-(4-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29, (R,S)7-(4-trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. 1H NMR (400 MHz, CDCl₃)δ 7.65 (s, 4H), 7.38 (d, J=8 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J=8 Hz,1H), 3.15 (m, 1H), 3.1-2.9 (m, 5H), 2.80 (dd, J=8, 13 Hz, 1H), 2.48 (bs,1H), 1.38 (d, J=8 Hz, 3H). MS calculated for C₁₈H₁₈F₃N+H: 306. observed:306.

Example 48 (R,S)8-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(84 mg, 0.229 mmol) in dimethylformamide (2.5 mL) was treated with2-chlorophenylboronic acid (43 mg, 0.275 mmol), CsF (52 mg, 0.34 mmol),water (70 mg, 3.9 mmol), Pd(PPh₃)₄ (27 mg, 0.023 mmol) and stirredovernight at 75 C. The product mixture was diluted with EtOAc (20 mL),washed with water (10 mL), brine (10 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (10-20% EtOAc in hexane, silica)resulted in 36 mg of a clear oil. MS calculated for C₁₉H₁₇ClF₃NO+H: 368.observed: 368. The product (39 mg, 0.106 mmol) was dissolved in methanol(2 mL) treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20C. The product mixture was concentrated, extracted 3 times with CH₂Cl₂(5 mL), dried with Na₂SO₄ and the solvent evaporated to give 18 mg of aclear oil. 1H NMR (400 MHz, CDCl₃) δ 7.44 (d, J=8 Hz, 1H), 7.35-7.17 (m,5H), 7.12 (d, J=8 Hz, 1H), 3.14 (m, 1H), 3.1-2.9 (m, 5H), 2.79 (dd, J=7,13 Hz, 1H), 2.36 (bs, 1H), 1.36 (d, J=7 Hz, 3H). MS calculated forC₁₇H₁₈ClN₃+H: 272. observed: 272.

Example 49 (R,S)7-Methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine(135 mg, 0.327 mmol) in dimethylformamide (3 mL) and toluene (0.5 mL)was treated with sodium trifluoroacetate (133 mg, 0.981 mmol), copper(I) iodide (124 mg, 0.654 mmol) and the toluene distilled off to removeany residual water. The reaction mixture was stirred at 155 C for 3.5hours, diluted with EtOAc, filtered, absorbed on silica and purified byflash chromatography (10% EtOAc in hexane, silica) resulting in 26 mg ofa colorless oil. MS calculated for C₁₅H₁₅F₆NO₂+H: 356. observed: 356.The intermediate (26 mg, 0.073 mmol) in methanol (2 mL) was treated with15% aqueous NaOH (2 mL), and stirred 0.5 hours at 50 C. The productmixture was diluted with water (5 mL), extracted twice with EtOAc (5mL), the combined organic phases were washed with brine (5 mL), driedwith Na₂SO₄ and concentrated to give 14 mg of a colorless oil. 1H NMR(400 MHz, CDCl₃) δ 7.32 (s, 1H), 6.73 (s, 1H), 3.89 (s, 3H), 3.1-2.9(bm, 6H), 2.75 (bm, 1H), 2.23 (bs, 1H), 1.36 (d, J=8 Hz, 3H). MScalculated for C₁₃H₁₆F₃NO+H: 260. observed: 260.

Example 50 (R,S)7-Methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine(100 mg, 0.242 mmol) in dimethylformamide (3 mL) and toluene (1 mL) wastreated with sodium pentafluoropropionate (64 mg, 0.344 mmol), copper(I) iodide (92 mg, 0.484 mmol) and the toluene distilled off to removeany residual water. The reaction mixture was stirred at 160 C for 3.5hours, diluted with EtOAc, filtered, absorbed on silica and purified byflash chromatography (10% EtOAc in hexane, silica) resulting in 22 mg ofa colorless oil. MS calculated for C₁₆H₁₅F₈NO₂+H: 406. observed: 406.The intermediate (22 mg, 0.054 mmol) in methanol (2 mL) was treated with15% aqueous NaOH (2 mL), and stirred 0.5 hours at 50 C. The productmixture was diluted with water (5 mL), extracted twice with EtOAc (5mL), the combined organic phases were washed with brine (5 mL), driedwith Na₂SO₄ and concentrated to give 14 mg of a colorless oil. 1H NMR(400 MHz, CDCl₃) δ 7.25 (s, 1H), 6.74 (s, 1H), 3.85 (s, 3H), 3.1-2.9(bm, 6H), 2.76 (bm, 1H), 2.37 (bs, 1H), 1.35 (d, J=8 Hz, 3H). MScalculated for C₁₄H₁₆F₅NO+H: 310. observed: 310.

Example 51 (R,S)8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26, (R,S)8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from 4-trifluoromethylphenethylamine as a colorless oil. 1H NMR(400 MHz, DMSO) δ 7.55 (d, J=8 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=8 Hz,1H), 3.55-3.50 (m, 1H) 3.43-3.23 (m, 7H), 3.13 (dd, J=16, 7 Hz, 1H),3.0-2.91 (m, 2H), 1.36 (d, J=7 Hz, 3H). MS calculated for C₁₂H₁₄F₃N+H:230.19. observed: 230.4

Example 52 (R,S)8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.075 g, 0.26 mmol) in dichloromethane (2 mL) was treated with BOC₂O(0.062 g, 0.29 mmol), and stirred overnight at 20 C. The product wasabsorbed on silica and purified by flash chromatography (33% EtOAc inhexane, silica) resulting in 0.034 g of a clear oil. MS calculated forC₁₇H₂₄BrNO₄+H: 386. observed: 386. The BOC-protected intermediate wasdissolved in dimethylformamide (1 mL), treated with excess NAH andexcess iodomethane sequentially, and then stirred for 1 hour at 20 C.The reaction mixture was quenched with water (5 mL), extracted twicewith EtOAc (5 mL), the combined organic phases were washed with brine (5mL), dried with Na₂SO₄ and concentrated to give 0.019 g of a clear oil.MS calculated for C₁₈H₂₆BrNO₄+H: 400. observed: 400. The N—BOC protectedmethylether was then treated with 4M HCl in dioxane (1 mL) and stirred 2hours at 20 C. Evaporation resulted in 0.009 g of the desired product asa clear oil. 1H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 6.92 (s, 1 H), 3.87(s, 3H), 3.65 (s, 3H) 3.5-3.1 (m, 9H). MS calculated for C₁₃H₁₈BrNO₂+H:300. observed: 300.

Example 53 (R,S) 8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Crotyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (6.2 g,15.8 mmol) in dimethylformamide (350 mL) was treated with K₂CO₃ (15.8 g,114 mmol) and crotyl bromide (6.0 g, 44 mmol) sequentially, the mixturewas stirred at 60 C for 16 hours and then cooled to 20 C. The mixturewas diluted with EtOAc (350 mL), washed with water (3×300 mL), driedwith Na₂SO₄ and concentrated. Flash chromatography (5-15% EtOAc inhexane) resulted in 2.5 g of a clear oil. MS calculated forC₁₄H₁₄ClF₃INO+H: 432. observed: 432.

N-Trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-crotyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine(2.5 g, 5.8 mmol) in dimethylformamide (250 mL) was treated with KOAc(1.07 g, 10.9 mmol), n-Bn₂Et₂NBr (1.33 g, 5.84 mmol), Pd(OAc)₂ (0.063 g,0.28 mmol) and stirred overnight at 77 C. The product mixture was cooledto 20 C, filtered, diluted with water (100 mL), extracted with EtOAc(3×100 mL), the combined organic phases washed with water (100 mL),brine (100 mL), dried with Na₂SO₄ and concentrated. Flash chromatography(2-20% EtOAc in hexane, silica) resulted in 0.339 g of a clear oil. Theproduct, which was assumed to be a mixture of double-bond isomers, wasdissolved in methanol (50 mL) treated with Et₃N (0.2 mL), 10% Pd/C (0.10g) and stirred 16 hours under 100 psi of hydrogen. The product mixturewas filtered, concentrated and purified by flash chromatography (5%EtOAc in hexane, silica) resulting in 0.20 g of a white solid. MScalculated for C₁₄H₁₅ClF₃NO+H: 306. observed: 306.

8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine(63 mg, 0.207 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 60 C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, DMSO-d₆)δ 7.2 (m, 3H), 3.3-3.0 (m, 7H), 1.9-1.6 (m, 2H), 0.91 (t, J=7 Hz, 3H).MS calculated for C₁₂H₁₆ClN+H: 210. observed: 210.

Example 54 (R,S)8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated withSelectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90mmol) and stirred 60 hours at 75 C. The product mixture was poured intowater (200 mL), extracted with EtOAc (200 mL), the organic phase washedwith saturated aqueous NaHCO₃ (2×100 mL), brine (100 mL), dried withNa₂SO₄ and concentrated. The crude product was purified by flashchromatography (6% EtOAc in hexane, silica) resulting in 1.6 g of awhite solid. MS calculated for C₁₃H₁₂ClF₄NO+H: 310. observed: 310.

8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 25 C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 93 mg of a clear oil. 1H NMR (400 MHz, CDCl₃) δ7.11 (m, 1H), 6.85 (m, 1H), 3.05-2.95 (m, 3H), 2.95-2.80 (m, 3H), 2.68(m, 1H), 2.38 (bm, 1H), 1.31 (m, 3H). MS calculated for C₁₁H₁₃ClFN+H:214. observed: 214.

Example 55 Separation of Enantiomers for Selected Compounds of theInvention

The following compounds were separated into their respective enantiomersusing a Varian ProStar HPLC system with a 20 mm×250 mm Chiralcel ODchiral column, eluting with 0.2% diethylamine in various concentrationsof isopropanol (IPA) in hexanes, see Table 1 below. In some cases, theseparations were performed on the intermediate trifluoroacetamideprotected amines.

TABLE 1 Retention time Retention time for the free for the ExampleEnantiomer amine (mins) trifluoroacetamide Conditions 1 1 21.9 5% IPA inhexane 2 24.5 10 mL/min 2 1 42 5% IPA in hexane 2 47  9 mL/min 3 1 20.85% IPA in hexane 2 24.2 10 mL/min 19 1 34.9 1% IPA in hexane 2 39.5  9mL/min 26 1 23.8 ¹ 5% IPA in hexane 2 29.2 ²  7 mL/min 37 1 23.8 ³ 5%IPA in hexane 2 29.2 ⁴  7 mL/min 51 1 18.6 ⁵ 1% IPA in hexane 2 21.4 ⁶ 9 mL/min 53 1 13.7 ⁷ 5% IPA in hexane 2 20.2 ⁸ 10 mL/min ¹ Theseparated trifluoroacetamide enantiomer was hydrolyzed to giveEnantiomer 1 of Compound 26. ² The separated trifluoroacetamideenantiomer was hydrolyzed to give Enantiomer 2 of Compound 26. ³ Theseparated trifluoroacetamide enantiomer was hydrolyzed and subsequentlyN-methylated to give Enantiomer 1 of Compound 37. ⁴ The separatedtrifluoroacetamide enantiomer was hydrolyzed and subsequentlyN-methylated to give Enantiomer 2 of Compound 37. ⁵ The separatedtrifluoroacetamide enantiomer was hydrolyzed to give Enantiomer 1 ofCompound 51. ⁶ The separated trifluoroacetamide enantiomer washydrolyzed to give Enantiomer 2 of Compound 51. ⁷ The separatedtrifluoroacetamide enantiomer was hydrolyzed to give Enantiomer 1 ofCompound 53. ⁸ The separated trifluoroacetamide enantiomer washydrolyzed to give Enantiomer 2 of Compound 53.

Example 56 Intracellular IP₃ Accumulation Assay

HEK293 cells were transfected in 15 cm sterile dishes with or without(control) 16 ug of human 5-HT_(2C) receptor cDNA using 25 ul oflipofectamine. Cells were then incubated for 3-4 hours at 37° C./5% CO₂and then transfection media was removed and replaced with 100 ul ofDMEM. Cells were then plated onto 100 cm sterile dishes. The next daycells were plated into 96 well PDL microtiter plates at a density of55K/0.2 ml. Six hours latter, media was exchanged with [³H]inositol(0.25 uCi/well) in inositol free DMEM and plates were incubated at 37°C./5% CO₂ overnight. The next day, wells were aspirated and 200 ul ofDMEM containing test compound, 10 uM pargyline, and 10 mM LiCl was addedto appropriate wells. Plates were then incubated at 37° C./5% CO₂ forthree hours followed aspiration and by addition of fresh ice cold stopsolution (1M KOH, 19 mM Na-borate, 3.8 mM EDTA) to each well. Plateswere kept on ice for 5-10 min and the wells were neutralized by additionof 200 ul of fresh ice cold neutralization solution (7.5% HCl). Plateswere then frozen until further processing is desired. The lysate wasthen transferred into 1.5 ml Eppendorf tubes and 1 ml ofchloroform/methanol (1:2) was added/tube. The solution was vortexed for15 seconds and the upper phase was applied to a Biorad AG1-X8™ anionexchange resin (100-200 mesh). First, the resin was washed with water at1:1.25 W/V and 0.9 ml of upper phase was loaded onto the column. Thecolumn was then washed with 10 ml of 5 mM myo-inositol and 10 ml of 5 mMNa-borate/60 mM Na-formate. The inositol tris phosphates were elutedinto scintillation vials containing 10 ml of scintillation cocktail with2 ml of 0.1 M formic acid/1 M ammonium formate. The columns wereregenerated by washing with 10 ml of 0.1 M formic acid/3M ammoniumformate and rinsed twice with dd H₂O and stored at 4° C. in water.

The biological activities in the IP Accumulation Assay for severalrepresentative compounds are shown in Table 2 below:

TABLE 2 Compound 5-HT_(2C) (IC₅₀)* (Example Number) IP AccumulationAssay (nM) 1 4.2 2 4.5 3 1.4 4 2.1 5 12.1 12 6.3 19 18 26 5.8 32 2.1*Reported values are averages of at least two trials.

The majority of the other compounds of the Examples were tested at leastonce, and they showed activities in the IP Accumulation Assay in therange between ˜1.4 nM and ˜5 μM.

Example 57 Inhibition of Food Intake in Food-Deprived Rats

Male Sprague-Dawley rats (250-350 g) were deprived of food overnightprior to testing. Prior to food deprivation, the animals were weighedand separated into treatment groups in order to balance groups accordingto body weight. On the test day, animals were placed into individualcages (no bedding) at 9:00 am with free access to water. At 10:00 am,animals were injected with test compound (p.o., i.p., or s.c.) and thenpresented with a pre-weighed amount of food in a dish either 60 min(p.o.) or 30 min (i.p. and s.c.) after drug administration. Foodconsumption over different time points was then determined by weighingthe food cup at 1, 2, 4, and 6 hr after the food was presented. Thus,food consumption was measured at 2, 3, 5, and 7 hr post-injection inp.o. studies, and at 1.5, 2.5, 4.5, and 6.5 hr post-injection in i.p.and s.c. studies.

FIGS. 1A-G illustrate the effects of seven different compounds on foodintake in food-deprived rats. All compounds inhibited food intakedose-dependently. This effect was consistently most pronounced over thefirst 1 hr after food presentation. Some compounds (FIGS. 1A, 1C, and1E) maintained an inhibitory effect on food intake relative tovehicle-treated controls at 6 hr after food presentation. Compounds werealso shown to be effective via all routes of administration includingp.o.

It is intended that each of the patents, applications, printedpublications, and other published documents mentioned or referred to inthis specification be herein incorporated by reference in theirentirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is therefore intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1-12. (canceled)
 13. A method for weight loss in an individual in needthereof, comprising administering an oral dose of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof to the individual.
 14. Themethod according to claim 13, wherein the dose is administered in theform of a tablet.
 15. The method according to claim 13, wherein themethod further comprises placing the individual on a diet.
 16. Themethod according to claim 13, wherein the method further comprisesincreasing the physical activity of the individual.
 17. The methodaccording to claim 13, wherein the individual has an initial body massindex (BMI) of 30 kg/m² or greater.
 18. The method according to claim13, wherein the individual has at least one weight-related conditionselected from: hypertension and type 2 diabetes.
 19. A method for weightloss in an individual in need thereof, comprising administering an oraldose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof to the individual, wherein the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orpharmaceutically acceptable salt thereof is administered in conjunctionwith a diet and increased physical activity.
 20. The method according toclaim 19, wherein the dose is administered in the form of a tablet. 21.The method according to claim 19, wherein the individual has an initialbody mass index (BMI) of 30 kg/m² or greater.
 22. The method accordingto claim 19, wherein the individual has at least one weight-relatedcondition selected from: hypertension and type 2 diabetes.
 23. A methodfor treating obesity in an individual in need thereof, comprisingadministering an oral dose of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof to the individual.
 24. Themethod according to claim 23, wherein the dose is administered in theform of a tablet.
 25. The method according to claim 23, wherein themethod further comprises placing the individual on a diet.
 26. Themethod according to claim 23, wherein the method further comprisesincreasing the physical activity of the individual.
 27. The methodaccording to claim 23, wherein the individual has at least oneweight-related condition selected from: hypertension and type 2diabetes.
 28. A method for treating obesity in an individual in needthereof, comprising administering an oral dose of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof, wherein the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orpharmaceutically acceptable salt thereof is administered in conjunctionwith a diet and increased physical activity.
 29. The method according toclaim 28, wherein the dose is administered in the form of a tablet. 30.The method according to claim 28, wherein the weight-related conditionis selected from: hypertension and type 2 diabetes.